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01-07-2016 | Original Article

RANK-RANKL interactions are involved in cell adhesion-mediated drug resistance in multiple myeloma cell lines

Authors: Masanobu Tsubaki, Tomoya Takeda, Misako Yoshizumi, Emi Ueda, Tatsuki Itoh, Motohiro Imano, Takao Satou, Shozo Nishida

Published in: Tumor Biology | Issue 7/2016

Abstract

Interaction between multiple myeloma (MM) cells and the bone marrow microenvironment plays a critical role in MM pathogenesis and the development of drug resistance. Recently, it has been reported that MM cells express the receptor activator of nuclear factor-κB (NF-κB) (RANK). However, the role of the RANK/RANK ligand (RANKL) system in drug resistance remains unclear. In this study, we demonstrated a novel function of the RANK/RANKL system in promoting drug resistance in MM. We found that RANKL treatment induced drug resistance in RANK-expressing but not RANK-negative cell lines. RANKL stimulation of RANK-expressing cells increased multidrug resistance protein 1 (MDR1), breast cancer resistance protein (BCRP), and lung resistance protein 1 (LRP1) expression and decreased Bim expression through various signaling molecules. RNA silencing of Bim expression induced drug resistance, but the RANKL-mediated drug resistance could not be overcome through the RNA silencing of MDR1, BCRP, and LRP1 expression. These results indicate that the RANK/RANKL system induces chemoresistance through the activation of multiple signal transduction pathways and by decreasing Bim expression in RANK-positive MM cells. These findings may prove to be useful in the development of cell adhesion-mediated drug resistance inhibitors in RANK-positive MM cells.

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Hideshima T, Mitsiades C, Tonon G, Richardson PG, Anderson KC. Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets. Nat Rev Cancer. 2007;7(8):585–98. doi:10.1038/nrc2189.CrossRefPubMed

Tsubaki M, Satou T, Itoh T, Imano M, Komai M, Nishinobo M, et al. Overexpression of MDR1 and survivin, and decreased Bim expression mediate multidrug-resistance in multiple myeloma cells. Leuk Res. 2012;36(10):1315–22. doi:10.1016/j.leukres.2012.07.003.CrossRefPubMed

Hazlehurst LA, Dalton WS. Mechanisms associated with cell adhesion mediated drug resistance (CAM-DR) in hematopoietic malignancies. Cancer Metastasis Rev. 2001;20(1-2):43–50. doi:10.1023/A:1013156407224.CrossRefPubMed

Hazlehurst LA, Enkemann SA, Beam CA, Argilagos RF, Painter J, Shain KH, et al. Genotypic and phenotypic comparisons of de novo and acquired melphalan resistance in an isogenic multiple myeloma cell line model. Cancer Res. 2003;63(22):7900–6.PubMed

Meads MB, Hazlehurst LA, Dalton WS. The bone marrow microenvironment as a tumor sanctuary and contributor to drug resistance. Clin Cancer Res. 2008;14(9):2519–26. doi:10.1158/1078-0432.CCR-07-2223.CrossRefPubMed

Damiano JS, Dalton WS. Integrin-mediated drug resistance in multiple myeloma. Leuk Lymphoma. 2000;38(1-2):71–81. doi:10.3109/10428190009060320.PubMed

Shain KH, Yarde DN, Meads MB, Huang M, Jove R, Hazlehurst LA, et al. Beta1 integrin adhesion enhances IL-6-mediated STAT3 signaling in myeloma cells: implications for microenvironment influence on tumor survival and proliferation. Cancer Res. 2009;69(3):1009–15. doi:10.1158/0008-5472.CAN-08-2419.CrossRefPubMedPubMedCentral

Eckford PD, Sharom FJ. ABC efflux pump-based resistance to chemotherapy drugs. Chem Rev. 2009;109(7):2989–3011.CrossRefPubMed

Mossink MH, van Zon A, Scheper RJ, Sonneveld P, Wiemer EA. Vaults: a ribonucleoprotein particle involved in drug resistance? Oncogene. 2003;22(47):7458–67.CrossRefPubMed

10.

Tsubaki M, Takeda T, Ogawa N, Sakamoto K, Shimaoka H, Fujita A, et al. Overexpression of survivin via activation of ERK1/2, Akt, and NF-κB plays a central role in vincristine resistance in multiple myeloma cells. Leuk Res. 2015;39(4):445–52. doi:10.1016/j.leukres.2015.01.016.CrossRefPubMed

11.

Tsubaki M, Komai M, Itoh T, Imano M, Sakamoto K, Shimaoka H, et al. By inhibiting Src, verapamil and dasatinib overcome multidrug resistance via increased expression of Bim and decreased expressions of MDR1 and survivin in human multidrug-resistant myeloma cells. Leuk Res. 2014;38(1):121–30. doi:10.1016/j.leukres.2013.CrossRefPubMed

12.

Tsubaki M, Komai M, Itoh T, Imano M, Sakamoto K, Shimaoka H, et al. Inhibition of the tumour necrosis factor-alpha autocrine loop enhances the sensitivity of multiple myeloma cells to anticancer drugs. Eur J Cancer. 2013;49(17):3708–17. doi:10.1016/j.ejca.2013.07.010.CrossRefPubMed

13.

Chen S, Zhang Y, Zhou L, Leng Y, Lin H, Kmieciak M, et al. A Bim-targeting strategy overcomes adaptive bortezomib resistance in myeloma through a novel link between autophagy and apoptosis. Blood. 2014;124(17):2687–97. doi:10.1182/blood-2014-03-564534.CrossRefPubMedPubMedCentral

14.

Murray ME, Gavile CM, Nair JR, Koorella C, Carlson LM, Buac D, et al. CD28-mediated pro-survival signaling induces chemotherapeutic resistance in multiple myeloma. Blood. 2014;123(24):3770–9. doi:10.1182/blood-2013-10-530964.CrossRefPubMedPubMedCentral

15.

Farrugia AN, Atkins GJ, To LB, Pan B, Horvath N, Kostakis P, et al. Receptor activator of nuclear factor-kappaB ligand expression by human myeloma cells mediates osteoclast formation in vitro and correlates with bone destruction in vivo. Cancer Res. 2003;63(17):5438–45.PubMed

16.

Sung B, Cho SG, Liu M, Aggarwal BB. Butein, a tetrahydroxychalcone, suppresses cancer-induced osteoclastogenesis through inhibition of receptor activator of nuclear factor-kappaB ligand signaling. Int J Cancer. 2011;129(9):2062–72. doi:10.1002/ijc.25868.CrossRefPubMedPubMedCentral

17.

Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature. 1999;397(6717):315–23. doi:10.1038/16852.CrossRefPubMed

18.

Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. 2003;423(6937):337–42. doi:10.1038/nature01658.CrossRefPubMed

19.

Tsubaki M, Komai M, Itoh T, Imano M, Sakamoto K, Shimaoka H, et al. Nitrogen-containing bisphosphonates inhibit RANKL- and M-CSF-induced osteoclast formation through the inhibition of ERK1/2 and Akt activation. J Biomed Sci. 2014;21:10. doi:10.1186/1423-0127-21-10.CrossRefPubMedPubMedCentral

20.

Gross S, Rahal R, Stransky N, Lengauer C, Hoeflich KP. Targeting cancer with kinase inhibitors. J Clin Invest. 2015;125(5):1780–9. doi:10.1172/JCI76094.CrossRefPubMedPubMedCentral

21.

Johnson KA, Brown PH. Drug development for cancer chemoprevention: focus on molecular targets. Semin Oncol. 2010;37(4):345–58. doi:10.1053/j.seminoncol.2010.05.012.CrossRefPubMed

22.

Sui H, Fan ZZ, Li Q. Signal transduction pathways and transcriptional mechanisms of ABCB1/Pgp-mediated multiple drug resistance in human cancer cells. J Int Med Res. 2012;40(2):426–35. doi:10.1177/147323001204000204.CrossRefPubMed

23.

Fiskus W, Pranpat M, Bali P, Balasis M, Kumaraswamy S, Boyapalle S, et al. Combined effects of novel tyrosine kinase inhibitor AMN107 and histone deacetylase inhibitor LBH589 against Bcr-Abl-expressing human leukemia cells. Blood. 2006;108(2):645–52. doi:10.1182/blood-2005-11-4639.CrossRefPubMed

24.

Fandy TE, Shankar S, Ross DD, Sausville E, Srivastava RK. Interactive effects of HDAC inhibitors and TRAIL on apoptosis are associated with changes in mitochondrial functions and expressions of cell cycle regulatory genes in multiple myeloma. Neoplasia. 2005;7(7):646–57.

25.

Lai FP, Cole-Sinclair M, Cheng WJ, Quinn JM, Gillespie MT, Sentry JW, et al. Myeloma cells can directly contribute to the pool of RANKL in bone bypassing the classic stromal and osteoblast pathway of osteoclast stimulation. Br J Haematol. 2004;126(2):192–201. doi:10.1111/j.1365-2141.2004.05018.x.CrossRefPubMed

26.

Calvani N, Cafforio P, Silvestris F, Dammacco F. Functional osteoclast-like transformation of cultured human myeloma cell lines. Br J Haematol. 2005;130(6):926–38. doi:10.1111/j.1365-2141.2005.05710.x.CrossRefPubMed

27.

Fiumara P, Snell V, Li Y, Mukhopadhyay A, Younes M, Gillenwater AM, et al. Functional expression of receptor activator of nuclear factor kappaB in Hodgkin disease cell lines. Blood. 2001;98(9):2784–90. doi:10.1182/blood.V98.9.2784.CrossRefPubMed

28.

Kukreja A, Hutchinson A, Dhodapkar K, Mazumder A, Vesole D, Angitapalli R, et al. Enhancement of clonogenicity of human multiple myeloma by dendritic cells. J Exp Med. 2006;203(8):1859–65. doi:10.1084/jem.20052136.CrossRefPubMedPubMedCentral

29.

Gonzalez-Suarez E, Jacob AP, Jones J, Miller R, Roudier-Meyer MP, Erwert R, et al. RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature. 2010;468(7320):103–7. doi:10.1038/nature09495.CrossRefPubMed

30.

Tsubaki M, Komai M, Fujimoto S, Itoh T, Imano M, Sakamoto K, et al. Activation of NF-κB by the RANKL/RANK system up-regulates snail and twist expressions and induces epithelial-to-mesenchymal transition in mammary tumor cell lines. J Exp Clin Cancer Res. 2013;32:62. doi:10.1186/1756-9966-32-62.CrossRefPubMedPubMedCentral

31.

Cote GM. Rank ligand as a target in musculoskeletal neoplasms. Curr Rev Musculoskelet Med. 2015;8:339–43. doi:10.1007/s12178-015-9310-y.CrossRefPubMedPubMedCentral

32.

Beristain AG, Narala SR, Di Grappa MA, Khokha R. Homotypic RANK signaling differentially regulates proliferation, motility and cell survival in osteosarcoma and mammary epithelial cells. J Cell Sci. 2012;125:943–55. doi:10.1242/jcs.094029.CrossRefPubMed

33.

Gonzalez-Suarez E, Branstetter D, Armstrong A, Dinh H, Blumberg H, Dougall WC. RANK overexpression in transgenic mice with mouse mammary tumor virus promoter-controlled RANK increases proliferation and impairs alveolar differentiation in the mammary epithelia and disrupts lumen formation in cultured epithelial acini. Mol Cell Biol. 2007;27:1442–54. doi:10.1128/MCB.01298-06.CrossRefPubMed

34.

Feng X. RANKing intracellular signaling in osteoclasts. IUBMB Life. 2005;57(6):389–95. doi:10.1080/15216540500137669.CrossRefPubMed

35.

Blair HC, Robinson LJ, Zaidi M. Osteoclast signalling pathways. Biochem Biophys Res Commun. 2005;328(3):728–38. doi:10.1016/j.bbrc.2004.11.077.CrossRefPubMed

36.

Galski H, Sivan H, Lazarovici P, Nagler A. In vitro and in vivo reversal of MDR1-mediated multidrug resistance by KT-5720: implications on hematological malignancies. Leuk Res. 2006;30(9):1151–8. doi:10.1016/j.leukres.2006.02.016.CrossRefPubMed

37.

Leung KT, Li KK, Sun SS, Chan PK, Ooi VE, Chiu LC. Activation of the JNK pathway promotes phosphorylation and degradation of BimEL—a novel mechanism of chemoresistance in T-cell acute lymphoblastic leukemia. Carcinogenesis. 2008;29(3):544–51. doi:10.1093/carcin/bgm294.CrossRefPubMed

38.

De Bruyne E, Bos TJ, Schuit F, Van Valckenborgh E, Menu E, Thorrez L, et al. IGF-1 suppresses Bim expression in multiple myeloma via epigenetic and posttranslational mechanisms. Blood. 2010;115(12):2430–40. doi:10.1182/blood-2009-07-232801.CrossRefPubMed

39.

Trudel S, Li ZH, Rauw J, Tiedemann RE, Wen XY, Stewart AK. Preclinical studies of the pan-Bcl inhibitor obatoclax (GX015-070) in multiple myeloma. Blood. 2007;109(12):5430–8. doi:10.1182/blood-2006-10-047951.CrossRefPubMed

Title: RANK-RANKL interactions are involved in cell adhesion-mediated drug resistance in multiple myeloma cell lines
Authors: Masanobu Tsubaki
Tomoya Takeda
Misako Yoshizumi
Emi Ueda
Tatsuki Itoh
Motohiro Imano
Takao Satou
Shozo Nishida
Publication date: 01-07-2016
Publisher: Springer Netherlands
Published in: Tumor Biology / Issue 7/2016
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI: https://doi.org/10.1007/s13277-015-4761-8

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