Top

Published in:

Open Access 01-12-2017

Proteasome-associated deubiquitinases and cancer

Authors: Arjan Mofers, Paola Pellegrini, Stig Linder, Pádraig D’Arcy

Published in: Cancer and Metastasis Reviews | Issue 4/2017

Abstract

Maintenance of protein homeostasis is a crucial process for the normal functioning of the cell. The regulated degradation of proteins is primarily facilitated by the ubiquitin proteasome system (UPS), a system of selective tagging of proteins with ubiquitin followed by proteasome-mediated proteolysis. The UPS is highly dynamic consisting of both ubiquitination and deubiquitination steps that modulate protein stabilization and degradation. Deregulation of protein stability is a common feature in the development and progression of numerous cancer types. Simultaneously, the elevated protein synthesis rate of cancer cells and consequential accumulation of misfolded proteins drives UPS addiction, thus sensitizing them to UPS inhibitors. This sensitivity along with the potential of stabilizing pro-apoptotic signaling pathways makes the proteasome an attractive clinical target for the development of novel therapies. Targeting of the catalytic 20S subunit of the proteasome is already a clinically validated strategy in multiple myeloma and other cancers. Spurred on by this success, promising novel inhibitors of the UPS have entered development, targeting the 20S as well as regulatory 19S subunit and inhibitors of deubiquitinating and ubiquitin ligase enzymes. In this review, we outline the manner in which deregulation of the UPS can cause cancer to develop, current clinical application of proteasome inhibitors, and the (pre-)clinical development of novel inhibitors of the UPS.

Herrmann, J., Ciechanover, A., Lerman, L. O., & Lerman, A. (2004). The ubiquitin-proteasome system in cardiovascular diseases—a hypothesis extended. Cardiovascular Research, 61(1), 11–21.PubMedCrossRef

Lehman, N. L. (2009). The ubiquitin proteasome system in neuropathology. Acta Neuropathologica, 118(3), 329–347. https://doi.org/10.1007/s00401-009-0560-x.PubMedPubMedCentralCrossRef

Li, W., Bengtson, M. H., Ulbrich, A., Matsuda, A., Reddy, V. A., Orth, A., et al. (2008). Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling. PLoS One, 3(1), e1487. https://doi.org/10.1371/journal.pone.0001487.PubMedPubMedCentralCrossRef

Komander, D. (2009). The emerging complexity of protein ubiquitination. Biochemical Society Transactions, 37(Pt 5), 937–953. https://doi.org/10.1042/BST0370937.PubMedCrossRef

Peterson, L. F., Sun, H., Liu, Y., Potu, H., Kandarpa, M., Ermann, M., et al. (2015). Targeting deubiquitinase activity with a novel small-molecule inhibitor as therapy for B-cell malignancies. Blood, 125(23), 3588–3597. https://doi.org/10.1182/blood-2014-10-605584.PubMedCrossRef

Reyes-Turcu, F. E., Ventii, K. H., & Wilkinson, K. D. (2009). Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes. Annual Review of Biochemistry, 78, 363–397. https://doi.org/10.1146/annurev.biochem.78.082307.091526.PubMedCrossRef

Amerik, A. Y., & Hochstrasser, M. (2004). Mechanism and function of deubiquitinating enzymes. Biochimica et Biophysica Acta, 1695(1–3), 189–207. https://doi.org/10.1016/j.bbamcr.2004.10.003.PubMedCrossRef

Balakirev, M. Y., Tcherniuk, S. O., Jaquinod, M., & Chroboczek, J. (2003). Otubains: a new family of cysteine proteases in the ubiquitin pathway. EMBO Reports, 4(5), 517–522. https://doi.org/10.1038/sj.embor.embor824.PubMedPubMedCentralCrossRef

Liu, C. W., & Jacobson, A. D. (2013). Functions of the 19S complex in proteasomal degradation. Trends in Biochemical Sciences, 38(2), 103–110. https://doi.org/10.1016/j.tibs.2012.11.009.PubMedPubMedCentralCrossRef

10.

Lam, Y. A., Xu, W., DeMartino, G. N., & Cohen, R. E. (1997). Editing of ubiquitin conjugates by an isopeptidase in the 26S proteasome. Nature, 385(6618), 737–740. https://doi.org/10.1038/385737a0.PubMedCrossRef

11.

Hamazaki, J., Iemura, S., Natsume, T., Yashiroda, H., Tanaka, K., & Murata, S. (2006). A novel proteasome interacting protein recruits the deubiquitinating enzyme UCH37 to 26S proteasomes. The EMBO Journal, 25(19), 4524–4536. https://doi.org/10.1038/sj.emboj.7601338.PubMedPubMedCentralCrossRef

12.

Yao, T., & Cohen, R. E. (2002). A cryptic protease couples deubiquitination and degradation by the proteasome. Nature, 419(6905), 403–407. https://doi.org/10.1038/nature01071.PubMedCrossRef

13.

Yao, T., Song, L., Xu, W., DeMartino, G. N., Florens, L., Swanson, S. K., et al. (2006). Proteasome recruitment and activation of the Uch37 deubiquitinating enzyme by Adrm1. Nature Cell Biology, 8(9), 994–1002. https://doi.org/10.1038/ncb1460.PubMedCrossRef

14.

Verma, R., Aravind, L., Oania, R., McDonald, W. H., Yates 3rd, J. R., Koonin, E. V., et al. (2002). Role of Rpn11 metalloprotease in deubiquitination and degradation by the 26S proteasome. Science, 298(5593), 611–615. https://doi.org/10.1126/science.1075898.PubMedCrossRef

15.

Groll, M., Ditzel, L., Lowe, J., Stock, D., Bochtler, M., Bartunik, H. D., et al. (1997). Structure of 20S proteasome from yeast at 2.4 Å resolution. Nature, 386(6624), 463–471. https://doi.org/10.1038/386463a0.PubMedCrossRef

16.

Unno, M., Mizushima, T., Morimoto, Y., Tomisugi, Y., Tanaka, K., Yasuoka, N., et al. (2002). The structure of the mammalian 20S proteasome at 2.75 Å resolution. Structure, 10(5), 609–618.PubMedCrossRef

17.

Kisselev, A. F., Akopian, T. N., Castillo, V., & Goldberg, A. L. (1999). Proteasome active sites allosterically regulate each other, suggesting a cyclical bite-chew mechanism for protein breakdown. Molecular Cell, 4(3), 395–402.PubMedCrossRef

18.

Micel, L. N., Tentler, J. J., Smith, P. G., & Eckhardt, G. S. (2013). Role of ubiquitin ligases and the proteasome in oncogenesis: novel targets for anticancer therapies. Journal of Clinical Oncology, 31(9), 1231–1238. https://doi.org/10.1200/JCO.2012.44.0958.PubMedPubMedCentralCrossRef

19.

D'Arcy, P., & Linder, S. (2014). Molecular pathways: translational potential of deubiquitinases as drug targets. Clinical Cancer Research, 20(15), 3908–3914. https://doi.org/10.1158/1078-0432.ccr-14-0568.PubMedCrossRef

20.

Laplante, M., & Sabatini, D. M. (2012). mTOR signaling in growth control and disease. Cell, 149(2), 274–293. https://doi.org/10.1016/j.cell.2012.03.017.PubMedPubMedCentralCrossRef

21.

Hartl, F. U., & Hayer-Hartl, M. (2009). Converging concepts of protein folding in vitro and in vivo. Nature Structural & Molecular Biology, 16(6), 574–581. https://doi.org/10.1038/nsmb.1591.CrossRef

22.

Tu, B. P., & Weissman, J. S. (2004). Oxidative protein folding in eukaryotes: mechanisms and consequences. The Journal of Cell Biology, 164(3), 341–346. https://doi.org/10.1083/jcb.200311055.PubMedPubMedCentralCrossRef

23.

Brnjic, S., Mazurkiewicz, M., Fryknas, M., Sun, C., Zhang, X., Larsson, R., et al. (2014). Induction of tumor cell apoptosis by a proteasome deubiquitinase inhibitor is associated with oxidative stress. Antioxidants & Redox Signaling, 21(17), 2271–2285. https://doi.org/10.1089/ars.2013.5322.CrossRef

24.

Fribley, A., & Wang, C. Y. (2006). Proteasome inhibitor induces apoptosis through induction of endoplasmic reticulum stress. Cancer Biology & Therapy, 5(7), 745–748.CrossRef

25.

Perez-Galan, P., Roue, G., Villamor, N., Montserrat, E., Campo, E., & Colomer, D. (2006). The proteasome inhibitor bortezomib induces apoptosis in mantle-cell lymphoma through generation of ROS and Noxa activation independent of p53 status. Blood, 107(1), 257–264. https://doi.org/10.1182/blood-2005-05-2091.PubMedCrossRef

26.

Ling, Y. H., Liebes, L., Zou, Y., & Perez-Soler, R. (2003). Reactive oxygen species generation and mitochondrial dysfunction in the apoptotic response to bortezomib, a novel proteasome inhibitor, in human H460 non-small cell lung cancer cells. The Journal of Biological Chemistry, 278(36), 33714–33723. https://doi.org/10.1074/jbc.M302559200.PubMedCrossRef

27.

Yu, C., Rahmani, M., Dent, P., & Grant, S. (2004). The hierarchical relationship between MAPK signaling and ROS generation in human leukemia cells undergoing apoptosis in response to the proteasome inhibitor bortezomib. Experimental Cell Research, 295(2), 555–566. https://doi.org/10.1016/j.yexcr.2004.02.001.PubMedCrossRef

28.

Hideshima, T., Ikeda, H., Chauhan, D., Okawa, Y., Raje, N., Podar, K., et al. (2009). Bortezomib induces canonical nuclear factor-kappaB activation in multiple myeloma cells. Blood, 114(5), 1046–1052. https://doi.org/10.1182/blood-2009-01-199604.PubMedPubMedCentralCrossRef

29.

Bedford, L., Lowe, J., Dick, L. R., Mayer, R. J., & Brownell, J. E. (2011). Ubiquitin-like protein conjugation and the ubiquitin-proteasome system as drug targets. Nature Reviews. Drug Discovery, 10(1), 29–46. https://doi.org/10.1038/nrd3321.PubMedCrossRef

30.

Yew, P. R. (2001). Ubiquitin-mediated proteolysis of vertebrate G1- and S-phase regulators. Journal of Cellular Physiology, 187(1), 1–10. https://doi.org/10.1002/1097-4652(2001)9999:9999<1::AID-JCP1049>3.0.CO;2-O.PubMedCrossRef

31.

Halazonetis, T. D., Gorgoulis, V. G., & Bartek, J. (2008). An oncogene-induced DNA damage model for cancer development. Science, 319(5868), 1352–1355. https://doi.org/10.1126/science.1140735.PubMedCrossRef

32.

Burgess, A., Chia, K. M., Haupt, S., Thomas, D., Haupt, Y., & Lim, E. (2016). Clinical overview of MDM2/X-targeted therapies. Frontiers in Oncology, 6, 7. https://doi.org/10.3389/fonc.2016.00007.PubMedPubMedCentralCrossRef

33.

Saha, M. N., Qiu, L., & Chang, H. (2013). Targeting p53 by small molecules in hematological malignancies. Journal of Hematology & Oncology, 6, 23. https://doi.org/10.1186/1756-8722-6-23.CrossRef

34.

Citri, A., Alroy, I., Lavi, S., Rubin, C., Xu, W., Grammatikakis, N., et al. (2002). Drug-induced ubiquitylation and degradation of ErbB receptor tyrosine kinases: implications for cancer therapy. The EMBO Journal, 21(10), 2407–2417. https://doi.org/10.1093/emboj/21.10.2407.PubMedPubMedCentralCrossRef

35.

Howell, A. (2006). Pure oestrogen antagonists for the treatment of advanced breast cancer. Endocrine-Related Cancer, 13(3), 689–706. https://doi.org/10.1677/erc.1.00846.PubMedCrossRef

36.

Salami, J., & Crews, C. M. (2017). Waste disposal—an attractive strategy for cancer therapy. Science, 355(6330), 1163–1167. https://doi.org/10.1126/science.aam7340.PubMedCrossRef

37.

Kumar, S. K., Bensinger, W. I., Zimmerman, T. M., Reeder, C. B., Berenson, J. R., Berg, D., et al. (2014). Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma. Blood, 124(7), 1047–1055. https://doi.org/10.1182/blood-2014-01-548941.PubMedPubMedCentralCrossRef

38.

Kontopodis, E., Kotsakis, A., Kentepozidis, N., Syrigos, K., Ziras, N., Moutsos, M., et al. (2016). A phase II, open-label trial of bortezomib (VELCADE((R))) in combination with gemcitabine and cisplatin in patients with locally advanced or metastatic non-small cell lung cancer. Cancer Chemotherapy and Pharmacology, 77(5), 949–956. https://doi.org/10.1007/s00280-016-2997-7.PubMedCrossRef

39.

Zhao, Y., Foster, N. R., Meyers, J. P., Thomas, S. P., Northfelt, D. W., Rowland Jr., K. M., et al. (2015). A phase I/II study of bortezomib in combination with paclitaxel, carboplatin, and concurrent thoracic radiation therapy for non-small-cell lung cancer: North Central Cancer Treatment Group (NCCTG)-N0321. Journal of Thoracic Oncology, 10(1), 172–180. https://doi.org/10.1097/JTO.0000000000000383.PubMedPubMedCentralCrossRef

40.

Chauhan, D., Hideshima, T., Mitsiades, C., Richardson, P., & Anderson, K. C. (2005). Proteasome inhibitor therapy in multiple myeloma. Molecular Cancer Therapeutics, 4(4), 686–692. https://doi.org/10.1158/1535-7163.MCT-04-0338.PubMedCrossRef

41.

Meister, S., Schubert, U., Neubert, K., Herrmann, K., Burger, R., Gramatzki, M., et al. (2007). Extensive immunoglobulin production sensitizes myeloma cells for proteasome inhibition. Cancer Research, 67(4), 1783–1792. https://doi.org/10.1158/0008-5472.CAN-06-2258.PubMedCrossRef

42.

Campo, E., & Rule, S. (2015). Mantle cell lymphoma: evolving management strategies. Blood, 125(1), 48–55. https://doi.org/10.1182/blood-2014-05-521898.PubMedCrossRef

43.

Jares, P., Colomer, D., & Campo, E. (2012). Molecular pathogenesis of mantle cell lymphoma. The Journal of Clinical Investigation, 122(10), 3416–3423. https://doi.org/10.1172/JCI61272.PubMedPubMedCentralCrossRef

44.

Kane, R. C., Bross, P. F., Farrell, A. T., & Pazdur, R. (2003). Velcade: U.S. FDA approval for the treatment of multiple myeloma progressing on prior therapy. The Oncologist, 8(6), 508–513.PubMedCrossRef

45.

Fisher, R. I., Bernstein, S. H., Kahl, B. S., Djulbegovic, B., Robertson, M. J., de Vos, S., et al. (2006). Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. Journal of Clinical Oncology, 24(30), 4867–4874. https://doi.org/10.1200/jco.2006.07.9665.PubMedCrossRef

46.

San Miguel, J. F., Schlag, R., Khuageva, N. K., Dimopoulos, M. A., Shpilberg, O., Kropff, M., et al. (2008). Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. The New England Journal of Medicine, 359(9), 906–917. https://doi.org/10.1056/NEJMoa0801479.PubMedCrossRef

47.

Adams, J. (2004). The development of proteasome inhibitors as anticancer drugs. Cancer Cell, 5(5), 417–421.PubMedCrossRef

48.

Sunwoo, J. B., Chen, Z., Dong, G., Yeh, N., Crowl Bancroft, C., Sausville, E., et al. (2001). Novel proteasome inhibitor PS-341 inhibits activation of nuclear factor-kappa B, cell survival, tumor growth, and angiogenesis in squamous cell carcinoma. Clinical Cancer Research, 7(5), 1419–1428.PubMed

49.

Hideshima, T., Richardson, P., Chauhan, D., Palombella, V. J., Elliott, P. J., Adams, J., et al. (2001). The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Research, 61(7), 3071–3076.PubMed

50.

Pham, L. V., Tamayo, A. T., Yoshimura, L. C., Lo, P., & Ford, R. J. (2003). Inhibition of constitutive NF-kappa B activation in mantle cell lymphoma B cells leads to induction of cell cycle arrest and apoptosis. Journal of Immunology, 171(1), 88–95.CrossRef

51.

Baiz, D., Pozzato, G., Dapas, B., Farra, R., Scaggiante, B., Grassi, M., et al. (2009). Bortezomib arrests the proliferation of hepatocellular carcinoma cells HepG2 and JHH6 by differentially affecting E2F1, p21 and p27 levels. Biochimie, 91(3), 373–382. https://doi.org/10.1016/j.biochi.2008.10.015.PubMedCrossRef

52.

Yang, Y., Ikezoe, T., Saito, T., Kobayashi, M., Koeffler, H. P., & Taguchi, H. (2004). Proteasome inhibitor PS-341 induces growth arrest and apoptosis of non-small cell lung cancer cells via the JNK/c-Jun/AP-1 signaling. Cancer Science, 95(2), 176–180.PubMedCrossRef

53.

Vaziri, S. A., Grabowski, D. R., Hill, J., Rybicki, L. R., Burk, R., Bukowski, R. M., et al. (2009). Inhibition of proteasome activity by bortezomib in renal cancer cells is p53 dependent and VHL independent. Anticancer Research, 29(8), 2961–2969.PubMedPubMedCentral

54.

Nikiforov, M. A., Riblett, M., Tang, W. H., Gratchouck, V., Zhuang, D., Fernandez, Y., et al. (2007). Tumor cell-selective regulation of NOXA by c-MYC in response to proteasome inhibition. Proceedings of the National Academy of Sciences of the United States of America, 104(49), 19488–19493. https://doi.org/10.1073/pnas.0708380104.PubMedPubMedCentralCrossRef

55.

Murray, M. Y., Auger, M. J., & Bowles, K. M. (2014). Overcoming bortezomib resistance in multiple myeloma. Biochemical Society Transactions, 42(4), 804–808. https://doi.org/10.1042/BST20140126.PubMedCrossRef

56.

Cavaletti, G., & Jakubowiak, A. J. (2010). Peripheral neuropathy during bortezomib treatment of multiple myeloma: a review of recent studies. Leukemia & Lymphoma, 51(7), 1178–1187. https://doi.org/10.3109/10428194.2010.483303.CrossRef

57.

Moreau, P., Pylypenko, H., Grosicki, S., Karamanesht, I., Leleu, X., Grishunina, M., et al. (2011). Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. The Lancet Oncology, 12(5), 431–440. https://doi.org/10.1016/S1470-2045(11)70081-X.PubMedCrossRef

58.

Moreau, P., Pylypenko, H., Grosicki, S., Karamanesht, I., Leleu, X., Rekhtman, G., et al. (2015). Subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma: subanalysis of patients with renal impairment in the phase III MMY-3021 study. Haematologica, 100(5), e207–e210. https://doi.org/10.3324/haematol.2014.118182.PubMedPubMedCentralCrossRef

59.

Arnulf, B., Pylypenko, H., Grosicki, S., Karamanesht, I., Leleu, X., van de Velde, H., et al. (2012). Updated survival analysis of a randomized phase III study of subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma. Haematologica, 97(12), 1925–1928. https://doi.org/10.3324/haematol.2012.067793.PubMedPubMedCentralCrossRef

60.

Wang, L., Wang, K. F., Chang, B. Y., Chen, X. Q., & Xia, Z. J. (2015). Once-weekly subcutaneous administration of bortezomib in patients with multiple myeloma. Asian Pacific Journal of Cancer Prevention, 16(5), 2093–2098.PubMedCrossRef

61.

Chen, D., Frezza, M., Schmitt, S., Kanwar, J., & Dou, Q. P. (2011). Bortezomib as the first proteasome inhibitor anticancer drug: current status and future perspectives. Current Cancer Drug Targets, 11(3), 239–253.PubMedPubMedCentralCrossRef

62.

Jagannath, S., Durie, B. G., Wolf, J., Camacho, E., Irwin, D., Lutzky, J., et al. (2005). Bortezomib therapy alone and in combination with dexamethasone for previously untreated symptomatic multiple myeloma. British Journal of Haematology, 129(6), 776–783. https://doi.org/10.1111/j.1365-2141.2005.05540.x.PubMedCrossRef

63.

Orlowski, R. Z., Voorhees, P. M., Garcia, R. A., Hall, M. D., Kudrik, F. J., Allred, T., et al. (2005). Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies. Blood, 105(8), 3058–3065. https://doi.org/10.1182/blood-2004-07-2911.PubMedCrossRef

64.

Hainsworth, J. D., Meluch, A. A., Spigel, D. R., Barton Jr., J., Simons, L., Meng, C., et al. (2007). Weekly docetaxel and bortezomib as first-line treatment for patients with hormone-refractory prostate cancer: a Minnie Pearl Cancer Research Network phase II trial. Clinical Genitourinary Cancer, 5(4), 278–283. https://doi.org/10.3816/CGC.2007.n.004.PubMedCrossRef

65.

Lu, S., Chen, Z., Yang, J., Chen, L., Gong, S., Zhou, H., et al. (2008). Overexpression of the PSMB5 gene contributes to bortezomib resistance in T-lymphoblastic lymphoma/leukemia cells derived from Jurkat line. Experimental Hematology, 36(10), 1278–1284. https://doi.org/10.1016/j.exphem.2008.04.013.PubMedCrossRef

66.

Lu, S., Yang, J., Chen, Z., Gong, S., Zhou, H., Xu, X., et al. (2009). Different mutants of PSMB5 confer varying bortezomib resistance in T lymphoblastic lymphoma/leukemia cells derived from the Jurkat cell line. Experimental Hematology, 37(7), 831–837. https://doi.org/10.1016/j.exphem.2009.04.001.PubMedCrossRef

67.

Oerlemans, R., Franke, N. E., Assaraf, Y. G., Cloos, J., van Zantwijk, I., Berkers, C. R., et al. (2008). Molecular basis of bortezomib resistance: proteasome subunit beta5 (PSMB5) gene mutation and overexpression of PSMB5 protein. Blood, 112(6), 2489–2499. https://doi.org/10.1182/blood-2007-08-104950.PubMedCrossRef

68.

Politou, M., Karadimitris, A., Terpos, E., Kotsianidis, I., Apperley, J. F., & Rahemtulla, A. (2006). No evidence of mutations of the PSMB5 (beta-5 subunit of proteasome) in a case of myeloma with clinical resistance to Bortezomib. Leukemia Research, 30(2), 240–241. https://doi.org/10.1016/j.leukres.2005.06.014.PubMedCrossRef

69.

Nawrocki, S. T., Carew, J. S., Pino, M. S., Highshaw, R. A., Andtbacka, R. H., Dunner Jr., K., et al. (2006). Aggresome disruption: a novel strategy to enhance bortezomib-induced apoptosis in pancreatic cancer cells. Cancer Research, 66(7), 3773–3781. https://doi.org/10.1158/0008-5472.CAN-05-2961.PubMedCrossRef

70.

Richardson, P. G., Schlossman, R. L., Alsina, M., Weber, D. M., Coutre, S. E., Gasparetto, C., et al. (2013). PANORAMA 2: panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma. Blood, 122(14), 2331–2337. https://doi.org/10.1182/blood-2013-01-481325.PubMedCrossRef

71.

Smith, A. J., Dai, H., Correia, C., Takahashi, R., Lee, S. H., Schmitz, I., et al. (2011). Noxa/Bcl-2 protein interactions contribute to bortezomib resistance in human lymphoid cells. The Journal of Biological Chemistry, 286(20), 17682–17692. https://doi.org/10.1074/jbc.M110.189092.PubMedPubMedCentralCrossRef

72.

Hagenbuchner, J., Ausserlechner, M. J., Porto, V., David, R., Meister, B., Bodner, M., et al. (2010). The anti-apoptotic protein BCL2L1/Bcl-xL is neutralized by pro-apoptotic PMAIP1/Noxa in neuroblastoma, thereby determining bortezomib sensitivity independent of prosurvival MCL1 expression. The Journal of Biological Chemistry, 285(10), 6904–6912. https://doi.org/10.1074/jbc.M109.038331.PubMedPubMedCentralCrossRef

73.

Premkumar, D. R., Jane, E. P., DiDomenico, J. D., Vukmer, N. A., Agostino, N. R., & Pollack, I. F. (2012). ABT-737 synergizes with bortezomib to induce apoptosis, mediated by Bid cleavage, Bax activation, and mitochondrial dysfunction in an Akt-dependent context in malignant human glioma cell lines. The Journal of Pharmacology and Experimental Therapeutics, 341(3), 859–872. https://doi.org/10.1124/jpet.112.191536.PubMedPubMedCentralCrossRef

74.

Zhang, L., Littlejohn, J. E., Cui, Y., Cao, X., Peddaboina, C., & Smythe, W. R. (2010). Characterization of bortezomib-adapted I-45 mesothelioma cells. Molecular Cancer, 9, 110. https://doi.org/10.1186/1476-4598-9-110.PubMedPubMedCentralCrossRef

75.

Herndon, T. M., Deisseroth, A., Kaminskas, E., Kane, R. C., Koti, K. M., Rothmann, M. D., et al. (2013). U.S. Food and Drug Administration approval: carfilzomib for the treatment of multiple myeloma. Clinical Cancer Research, 19(17), 4559–4563. https://doi.org/10.1158/1078-0432.CCR-13-0755.PubMedCrossRef

76.

Kuhn, D. J., Chen, Q., Voorhees, P. M., Strader, J. S., Shenk, K. D., Sun, C. M., et al. (2007). Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood, 110(9), 3281–3290. https://doi.org/10.1182/blood-2007-01-065888.PubMedPubMedCentralCrossRef

77.

Parlati, F., Lee, S. J., Aujay, M., Suzuki, E., Levitsky, K., Lorens, J. B., et al. (2009). Carfilzomib can induce tumor cell death through selective inhibition of the chymotrypsin-like activity of the proteasome. Blood, 114(16), 3439–3447. https://doi.org/10.1182/blood-2009-05-223677.PubMedCrossRef

78.

Demo, S. D., Kirk, C. J., Aujay, M. A., Buchholz, T. J., Dajee, M., Ho, M. N., et al. (2007). Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Research, 67(13), 6383–6391. https://doi.org/10.1158/0008-5472.CAN-06-4086.PubMedCrossRef

79.

Kisselev, A. F., & Goldberg, A. L. (2001). Proteasome inhibitors: from research tools to drug candidates. Chemistry & Biology, 8(8), 739–758.CrossRef

80.

Mitsiades, C. S., Hayden, P. J., Anderson, K. C., & Richardson, P. G. (2007). From the bench to the bedside: emerging new treatments in multiple myeloma. Best Practice & Research. Clinical Haematology, 20(4), 797–816. https://doi.org/10.1016/j.beha.2007.09.008.CrossRef

81.

Jakubowiak, A. J. (2014). Evolution of carfilzomib dose and schedule in patients with multiple myeloma: a historical overview. Cancer Treatment Reviews, 40(6), 781–790. https://doi.org/10.1016/j.ctrv.2014.02.005.PubMedCrossRef

82.

Berenson, J. R., Cartmell, A., Bessudo, A., Lyons, R. M., Harb, W., Tzachanis, D., et al. (2016). CHAMPION-1: a phase 1/2 study of once-weekly carfilzomib and dexamethasone for relapsed or refractory multiple myeloma. Blood, 127(26), 3360–3368. https://doi.org/10.1182/blood-2015-11-683854.PubMedPubMedCentralCrossRef

83.

Lendvai, N., Hilden, P., Devlin, S., Landau, H., Hassoun, H., Lesokhin, A. M., et al. (2014). A phase 2 single-center study of carfilzomib 56 mg/m2 with or without low-dose dexamethasone in relapsed multiple myeloma. Blood, 124(6), 899–906. https://doi.org/10.1182/blood-2014-02-556308.PubMedPubMedCentralCrossRef

84.

Siegel, D., Martin, T., Nooka, A., Harvey, R. D., Vij, R., Niesvizky, R., et al. (2013). Integrated safety profile of single-agent carfilzomib: experience from 526 patients enrolled in 4 phase II clinical studies. Haematologica, 98(11), 1753–1761. https://doi.org/10.3324/haematol.2013.089334.PubMedPubMedCentralCrossRef

85.

Zhou, H. J., Aujay, M. A., Bennett, M. K., Dajee, M., Demo, S. D., Fang, Y., et al. (2009). Design and synthesis of an orally bioavailable and selective peptide epoxyketone proteasome inhibitor (PR-047). Journal of Medicinal Chemistry, 52(9), 3028–3038. https://doi.org/10.1021/jm801329v.PubMedCrossRef

86.

Chauhan, D., Singh, A. V., Aujay, M., Kirk, C. J., Bandi, M., Ciccarelli, B., et al. (2010). A novel orally active proteasome inhibitor ONX 0912 triggers in vitro and in vivo cytotoxicity in multiple myeloma. Blood, 116(23), 4906–4915. https://doi.org/10.1182/blood-2010-04-276626.PubMedPubMedCentralCrossRef

87.

Zang, Y., Thomas, S. M., Chan, E. T., Kirk, C. J., Freilino, M. L., DeLancey, H. M., et al. (2012). Carfilzomib and ONX 0912 inhibit cell survival and tumor growth of head and neck cancer and their activities are enhanced by suppression of Mcl-1 or autophagy. Clinical Cancer Research, 18(20), 5639–5649. https://doi.org/10.1158/1078-0432.CCR-12-1213.PubMedPubMedCentralCrossRef

88.

Roccaro, A. M., Sacco, A., Aujay, M., Ngo, H. T., Azab, A. K., Azab, F., et al. (2010). Selective inhibition of chymotrypsin-like activity of the immunoproteasome and constitutive proteasome in Waldenstrom macroglobulinemia. Blood, 115(20), 4051–4060. https://doi.org/10.1182/blood-2009-09-243402.PubMedPubMedCentralCrossRef

89.

Hurchla, M. A., Garcia-Gomez, A., Hornick, M. C., Ocio, E. M., Li, A., Blanco, J. F., et al. (2013). The epoxyketone-based proteasome inhibitors carfilzomib and orally bioavailable oprozomib have anti-resorptive and bone-anabolic activity in addition to anti-myeloma effects. Leukemia, 27(2), 430–440. https://doi.org/10.1038/leu.2012.183.PubMedCrossRef

90.

Infante, J. R., Mendelson, D. S., Burris 3rd, H. A., Bendell, J. C., Tolcher, A. W., Gordon, M. S., et al. (2016). A first-in-human dose-escalation study of the oral proteasome inhibitor oprozomib in patients with advanced solid tumors. Investigational New Drugs, 34(2), 216–224. https://doi.org/10.1007/s10637-016-0327-x.PubMedCrossRef

91.

Muz, B., Ghazarian, R. N., Ou, M., Luderer, M. J., Kusdono, H. D., & Azab, A. K. (2016). Spotlight on ixazomib: potential in the treatment of multiple myeloma. Drug Design, Development and Therapy, 10, 217–226. https://doi.org/10.2147/DDDT.S93602.PubMedPubMedCentral

92.

Offidani, M., Corvatta, L., Caraffa, P., Gentili, S., Maracci, L., & Leoni, P. (2014). An evidence-based review of ixazomib citrate and its potential in the treatment of newly diagnosed multiple myeloma. Onco Targets Ther, 7, 1793–1800. https://doi.org/10.2147/OTT.S49187.PubMedPubMedCentralCrossRef

93.

Kupperman, E., Lee, E. C., Cao, Y., Bannerman, B., Fitzgerald, M., Berger, A., et al. (2010). Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer. Cancer Research, 70(5), 1970–1980. https://doi.org/10.1158/0008-5472.CAN-09-2766.PubMedCrossRef

94.

Lee, E. C., Fitzgerald, M., Bannerman, B., Donelan, J., Bano, K., Terkelsen, J., et al. (2011). Antitumor activity of the investigational proteasome inhibitor MLN9708 in mouse models of B-cell and plasma cell malignancies. Clinical Cancer Research, 17(23), 7313–7323. https://doi.org/10.1158/1078-0432.CCR-11-0636.PubMedPubMedCentralCrossRef

95.

Chauhan, D., Tian, Z., Zhou, B., Kuhn, D., Orlowski, R., Raje, N., et al. (2011). In vitro and in vivo selective antitumor activity of a novel orally bioavailable proteasome inhibitor MLN9708 against multiple myeloma cells. Clinical Cancer Research, 17(16), 5311–5321. https://doi.org/10.1158/1078-0432.CCR-11-0476.PubMedPubMedCentralCrossRef

96.

Tian, Z., Zhao, J. J., Tai, Y. T., Amin, S. B., Hu, Y., Berger, A. J., et al. (2012). Investigational agent MLN9708/2238 targets tumor-suppressor miR33b in MM cells. Blood, 120(19), 3958–3967. https://doi.org/10.1182/blood-2012-01-401794.PubMedPubMedCentralCrossRef

97.

Kumar, S. K., Berdeja, J. G., Niesvizky, R., Lonial, S., Laubach, J. P., Hamadani, M., et al. (2014). Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study. The Lancet Oncology, 15(13), 1503–1512. https://doi.org/10.1016/S1470-2045(14)71125-8.PubMedCrossRef

98.

D'Arcy, P., Brnjic, S., Olofsson, M. H., Fryknas, M., Lindsten, K., De Cesare, M., et al. (2011). Inhibition of proteasome deubiquitinating activity as a new cancer therapy. Nature Medicine, 17(12), 1636–1640. https://doi.org/10.1038/nm.2536.PubMedCrossRef

99.

Wang, X., Stafford, W., Mazurkiewicz, M., Fryknas, M., Brjnic, S., Zhang, X., et al. (2014). The 19S deubiquitinase inhibitor b-AP15 is enriched in cells and elicits rapid commitment to cell death. Molecular Pharmacology, 85(6), 932–945. https://doi.org/10.1124/mol.113.091322.PubMedCrossRef

100.

Paulus, A., Chitta, K., Akhtar, S., Personett, D., Miller, K. C., Thompson, K. J., et al. (2014). AT-101 downregulates BCL2 and MCL1 and potentiates the cytotoxic effects of lenalidomide and dexamethasone in preclinical models of multiple myeloma and Waldenstrom macroglobulinaemia. British Journal of Haematology, 164(3), 352–365. https://doi.org/10.1111/bjh.12633.PubMedCrossRef

101.

Wang, X., Mazurkiewicz, M., Hillert, E. K., Olofsson, M. H., Pierrou, S., Hillertz, P., et al. (2016). The proteasome deubiquitinase inhibitor VLX1570 shows selectivity for ubiquitin-specific protease-14 and induces apoptosis of multiple myeloma cells. Scientific Reports, 6, 26979. https://doi.org/10.1038/srep26979.PubMedPubMedCentralCrossRef

102.

Selvaraju, K., Mazurkiewicz, M., Wang, X., Gullbo, J., Linder, S., & D'Arcy, P. (2015). Inhibition of proteasome deubiquitinase activity: a strategy to overcome resistance to conventional proteasome inhibitors? Drug Resistance Updates, 21-22, 20–29. https://doi.org/10.1016/j.drup.2015.06.001.PubMedCrossRef

103.

Bartholomeusz, G. A., Talpaz, M., Kapuria, V., Kong, L. Y., Wang, S., Estrov, Z., et al. (2007). Activation of a novel Bcr/Abl destruction pathway by WP1130 induces apoptosis of chronic myelogenous leukemia cells. Blood, 109(8), 3470–3478. https://doi.org/10.1182/blood-2006-02-005579.PubMedPubMedCentralCrossRef

104.

Bartholomeusz, G., Talpaz, M., Bornmann, W., Kong, L. Y., & Donato, N. J. (2007). Degrasyn activates proteasomal-dependent degradation of c-Myc. Cancer Research, 67(8), 3912–3918. https://doi.org/10.1158/0008-5472.CAN-06-4464.PubMedCrossRef

105.

Schwickart, M., Huang, X., Lill, J. R., Liu, J., Ferrando, R., French, D. M., et al. (2010). Deubiquitinase USP9X stabilizes MCL1 and promotes tumour cell survival. Nature, 463(7277), 103–107. https://doi.org/10.1038/nature08646.PubMedCrossRef

106.

Chauhan, D., Tian, Z., Nicholson, B., Kumar, K. G., Zhou, B., Carrasco, R., et al. (2012). A small molecule inhibitor of ubiquitin-specific protease-7 induces apoptosis in multiple myeloma cells and overcomes bortezomib resistance. Cancer Cell, 22(3), 345–358. https://doi.org/10.1016/j.ccr.2012.08.007.PubMedPubMedCentralCrossRef

107.

Malapelle, U., Morra, F., Ilardi, G., Visconti, R., Merolla, F., Cerrato, A., et al. (2017). USP7 inhibitors, downregulating CCDC6, sensitize lung neuroendocrine cancer cells to PARP-inhibitor drugs. Lung Cancer, 107, 41–49. https://doi.org/10.1016/j.lungcan.2016.06.015.PubMedCrossRef

108.

Morra, F., Merolla, F., Napolitano, V., Ilardi, G., Miro, C., Paladino, S., et al. (2017). The combined effect of USP7 inhibitors and PARP inhibitors in hormone-sensitive and castration-resistant prostate cancer cells. Oncotarget, 8(19), 31815–31829. 10.18632/oncotarget.16463.PubMedPubMedCentral

109.

An, T., Gong, Y., Li, X., Kong, L., Ma, P., Gong, L., et al. (2017). USP7 inhibitor P5091 inhibits Wnt signaling and colorectal tumor growth. Biochemical Pharmacology, 131, 29–39. https://doi.org/10.1016/j.bcp.2017.02.011.PubMedCrossRef

110.

Carra, G., Panuzzo, C., Torti, D., Parvis, G., Crivellaro, S., Familiari, U., et al. (2017). Therapeutic inhibition of USP7-PTEN network in chronic lymphocytic leukemia: a strategy to overcome TP53 mutated/deleted clones. Oncotarget. 10.18632/oncotarget.16348.

111.

Das, D. S., Ray, A., Das, A., Song, Y., Tian, Z., Oronsky, B., et al. (2016). A novel hypoxia-selective epigenetic agent RRx-001 triggers apoptosis and overcomes drug resistance in multiple myeloma cells. Leukemia, 30(11), 2187–2197. https://doi.org/10.1038/leu.2016.96.PubMedPubMedCentralCrossRef

112.

Scicinski, J., Oronsky, B., Ning, S., Knox, S., Peehl, D., Kim, M. M., et al. (2015). NO to cancer: The complex and multifaceted role of nitric oxide and the epigenetic nitric oxide donor, RRx-001. Redox Biology, 6, 1–8. https://doi.org/10.1016/j.redox.2015.07.002.PubMedPubMedCentralCrossRef

113.

Ning, S., Sekar, T. V., Scicinski, J., Oronsky, B., Peehl, D. M., Knox, S. J., et al. (2015). Nrf2 activity as a potential biomarker for the pan-epigenetic anticancer agent, RRx-001. Oncotarget, 6(25), 21547–21556. 10.18632/oncotarget.4249.PubMedPubMedCentralCrossRef

114.

Byun, S., Lee, S. Y., Lee, J., Jeong, C. H., Farrand, L., Lim, S., et al. (2013). USP8 is a novel target for overcoming gefitinib resistance in lung cancer. Clinical Cancer Research, 19(14), 3894–3904. https://doi.org/10.1158/1078-0432.CCR-12-3696.PubMedPubMedCentralCrossRef

115.

Pao, W., Miller, V. A., Politi, K. A., Riely, G. J., Somwar, R., Zakowski, M. F., et al. (2005). Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Medicine, 2(3), e73. https://doi.org/10.1371/journal.pmed.0020073.PubMedPubMedCentralCrossRef

116.

Cichewicz, R. H., & Kouzi, S. A. (2004). Chemistry, biological activity, and chemotherapeutic potential of betulinic acid for the prevention and treatment of cancer and HIV infection. Medicinal Research Reviews, 24(1), 90–114. https://doi.org/10.1002/med.10053.PubMedCrossRef

117.

Mullauer, F. B., Kessler, J. H., & Medema, J. P. (2010). Betulinic acid, a natural compound with potent anticancer effects. Anti-Cancer Drugs, 21(3), 215–227. https://doi.org/10.1097/CAD.0b013e3283357c62.PubMedCrossRef

118.

Reiner, T., Parrondo, R., de Las Pozas, A., Palenzuela, D., & Perez-Stable, C. (2013). Betulinic acid selectively increases protein degradation and enhances prostate cancer-specific apoptosis: possible role for inhibition of deubiquitinase activity. PLoS One, 8(2), e56234. https://doi.org/10.1371/journal.pone.0056234.PubMedPubMedCentralCrossRef

119.

Potze, L., Di Franco, S., Grandela, C., Pras-Raves, M. L., Picavet, D. I., van Veen, H. A., et al. (2016). Betulinic acid induces a novel cell death pathway that depends on cardiolipin modification. Oncogene, 35(4), 427–437. https://doi.org/10.1038/onc.2015.102.PubMedCrossRef

120.

Currie, E., Schulze, A., Zechner, R., Walther, T. C., & Farese Jr., R. V. (2013). Cellular fatty acid metabolism and cancer. Cell Metabolism, 18(2), 153–161. https://doi.org/10.1016/j.cmet.2013.05.017.PubMedPubMedCentralCrossRef

121.

Li, J., Yakushi, T., Parlati, F., Mackinnon, A. L., Perez, C., Ma, Y., et al. (2017). Capzimin is a potent and specific inhibitor of proteasome isopeptidase Rpn11. Nature Chemical Biology, 13(5), 486–493. https://doi.org/10.1038/nchembio.2326.PubMedPubMedCentralCrossRef

122.

Cohen, S. M. (2017). A bioinorganic approach to fragment-based drug discovery targeting metalloenzymes. Accounts of Chemical Research. https://doi.org/10.1021/acs.accounts.7b00242.

123.

Brownell, J. E., Sintchak, M. D., Gavin, J. M., Liao, H., Bruzzese, F. J., Bump, N. J., et al. (2010). Substrate-assisted inhibition of ubiquitin-like protein-activating enzymes: the NEDD8 E1 inhibitor MLN4924 forms a NEDD8-AMP mimetic in situ. Molecular Cell, 37(1), 102–111. https://doi.org/10.1016/j.molcel.2009.12.024.PubMedCrossRef

124.

Soucy, T. A., Smith, P. G., Milhollen, M. A., Berger, A. J., Gavin, J. M., Adhikari, S., et al. (2009). An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature, 458(7239), 732–736. https://doi.org/10.1038/nature07884.PubMedCrossRef

125.

Shah, J. J., Jakubowiak, A. J., O'Connor, O. A., Orlowski, R. Z., Harvey, R. D., Smith, M. R., et al. (2016). Phase I study of the novel investigational NEDD8-activating enzyme inhibitor pevonedistat (MLN4924) in patients with relapsed/refractory multiple myeloma or lymphoma. Clinical Cancer Research, 22(1), 34–43. https://doi.org/10.1158/1078-0432.CCR-15-1237.PubMedCrossRef

126.

Bhatia, S., Pavlick, A. C., Boasberg, P., Thompson, J. A., Mulligan, G., Pickard, M. D., et al. (2016). A phase I study of the investigational NEDD8-activating enzyme inhibitor pevonedistat (TAK-924/MLN4924) in patients with metastatic melanoma. Investigational New Drugs, 34(4), 439–449. https://doi.org/10.1007/s10637-016-0348-5.PubMedPubMedCentralCrossRef

127.

Sarantopoulos, J., Shapiro, G. I., Cohen, R. B., Clark, J. W., Kauh, J. S., Weiss, G. J., et al. (2016). Phase I study of the investigational NEDD8-activating enzyme inhibitor pevonedistat (TAK-924/MLN4924) in patients with advanced solid tumors. Clinical Cancer Research, 22(4), 847–857. https://doi.org/10.1158/1078-0432.CCR-15-1338.PubMedCrossRef

128.

Xu, G. W., Ali, M., Wood, T. E., Wong, D., Maclean, N., Wang, X., et al. (2010). The ubiquitin-activating enzyme E1 as a therapeutic target for the treatment of leukemia and multiple myeloma. Blood, 115(11), 2251–2259. https://doi.org/10.1182/blood-2009-07-231191.PubMedPubMedCentralCrossRef

129.

Yang, Y., Kitagaki, J., Dai, R. M., Tsai, Y. C., Lorick, K. L., Ludwig, R. L., et al. (2007). Inhibitors of ubiquitin-activating enzyme (E1), a new class of potential cancer therapeutics. Cancer Research, 67(19), 9472–9481. https://doi.org/10.1158/0008-5472.CAN-07-0568.PubMedCrossRef

130.

Ungermannova, D., Parker, S. J., Nasveschuk, C. G., Chapnick, D. A., Phillips, A. J., Kuchta, R. D., et al. (2012). Identification and mechanistic studies of a novel ubiquitin E1 inhibitor. Journal of Biomolecular Screening, 17(4), 421–434. https://doi.org/10.1177/1087057111433843.PubMedPubMedCentralCrossRef

131.

Asuthkar, S., Velpula, K. K., Elustondo, P. A., Demirkhanyan, L., & Zakharian, E. (2015). TRPM8 channel as a novel molecular target in androgen-regulated prostate cancer cells. Oncotarget, 6(19), 17221–17236. 10.18632/oncotarget.3948.PubMedPubMedCentralCrossRef

132.

Grace, C. R., Ban, D., Min, J., Mayasundari, A., Min, L., Finch, K. E., et al. (2016). Monitoring ligand-induced protein ordering in drug discovery. Journal of Molecular Biology, 428(6), 1290–1303. https://doi.org/10.1016/j.jmb.2016.01.016.PubMedPubMedCentralCrossRef

133.

Zheng, T., Wang, J., Song, X., Meng, X., Pan, S., Jiang, H., et al. (2010). Nutlin-3 cooperates with doxorubicin to induce apoptosis of human hepatocellular carcinoma cells through p53 or p73 signaling pathways. Journal of Cancer Research and Clinical Oncology, 136(10), 1597–1604. https://doi.org/10.1007/s00432-010-0817-8.PubMedCrossRef

134.

Roh, J. L., Kang, S. K., Minn, I., Califano, J. A., Sidransky, D., & Koch, W. M. (2011). p53-reactivating small molecules induce apoptosis and enhance chemotherapeutic cytotoxicity in head and neck squamous cell carcinoma. Oral Oncology, 47(1), 8–15. https://doi.org/10.1016/j.oraloncology.2010.10.011.PubMedCrossRef

135.

Endo, S., Yamato, K., Hirai, S., Moriwaki, T., Fukuda, K., Suzuki, H., et al. (2011). Potent in vitro and in vivo antitumor effects of MDM2 inhibitor nutlin-3 in gastric cancer cells. Cancer Science, 102(3), 605–613. https://doi.org/10.1111/j.1349-7006.2010.01821.x.PubMedCrossRef

136.

Vassilev, L. T., Vu, B. T., Graves, B., Carvajal, D., Podlaski, F., Filipovic, Z., et al. (2004). In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science, 303(5659), 844–848. https://doi.org/10.1126/science.1092472.PubMedCrossRef

137.

Khoo, K. H., Verma, C. S., & Lane, D. P. (2014). Drugging the p53 pathway: understanding the route to clinical efficacy. Nature Reviews. Drug Discovery, 13(3), 217–236. https://doi.org/10.1038/nrd4236.PubMedCrossRef

138.

Lee, Y. M., Lim, J. H., Chun, Y. S., Moon, H. E., Lee, M. K., Huang, L. E., et al. (2009). Nutlin-3, an Hdm2 antagonist, inhibits tumor adaptation to hypoxia by stimulating the FIH-mediated inactivation of HIF-1alpha. Carcinogenesis, 30(10), 1768–1775. https://doi.org/10.1093/carcin/bgp196.PubMedCrossRef

Title: Proteasome-associated deubiquitinases and cancer
Authors: Arjan Mofers
Paola Pellegrini
Stig Linder
Pádraig D’Arcy
Publication date: 01-12-2017
Publisher: Springer US
Published in: Cancer and Metastasis Reviews / Issue 4/2017
Print ISSN: 0167-7659
Electronic ISSN: 1573-7233
DOI: https://doi.org/10.1007/s10555-017-9697-6

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 4/2017

The ubiquitin-proteasome pathway in adult and pediatric brain tumors: biological insights and therapeutic opportunities

Preface

Myristoylated alanine-rich C kinase substrate (MARCKS): a multirole signaling protein in cancers

Biography—Q. Ping Dou

Ubiquitin carboxyl-terminal hydrolases: involvement in cancer progression and clinical implications

The proteasome and proteasome inhibitors in multiple myeloma

Keynote webinar | Spotlight on antibody–drug conjugates in cancer