Top

Cancer Chemotherapy and Pharmacology

Published in:

01-03-2022 | Glioblastoma | Original Article

Isoprenylcysteine carboxyl methyltransferase is critical for glioblastoma growth and survival by activating Ras/Raf/Mek/Erk

Authors: Weifeng Wan, Wenfeng Xiao, Wen Pan, Ligang Chen, Zhiyong Liu, Jianguo Xu

Published in: Cancer Chemotherapy and Pharmacology | Issue 3/2022

Abstract

Purpose

The poor outcomes in glioblastoma necessitate new therapeutic target. Isoprenylcysteine carboxyl methyltransferase (ICMT), a unique enzyme of the final step of prenylation that modifies activities of oncogenic proteins, represents a promising target for many cancers.

Methods

Expression pattern, function and downstream pathway of ICMT in glioblastoma were analyzed using immunohistochemistry, ELISA, cellular assays and immunoblotting method. Combinatory effect was analyzed using Chou-Talalay approach.

Results

Upregulation of ICMT expression is a common phenomenon in glioblastoma patients regardless of clinicopathological characteristics. Gain-of-function and loss-of-function analysis support the role of ICMT in glioblastoma growth and survival but not migration. Importantly, pharmacological inhibitors of ICMT are effectively against glioblastoma cells while sparing normal neuron cells, and furthermore that they act synergistically with chemotherapeutic drugs. Consistently, ICMT inhibitor UCM-1336 significantly inhibits glioblastoma growth without causing toxicity in mice. Mechanistic studies demonstrate that Ras/Raf/Mek/Erk rather than Ras/PI3K/Akt/mTOR is the downstream pathway of ICMT-mediated glioblastoma growth.

Conclusions

Our findings provide the proof-of-concept of pharmacologically targeting ICMT in the treatment of glioblastoma via deactivation of Ras/Raf/Mek/Erk.

Available only for authorised users

Batash R, Asna N, Schaffer P, Francis N, Schaffer M (2017) Glioblastoma multiforme, diagnosis and treatment recent literature review. Curr Med Chem 24(27):3002–3009. https://doi.org/10.2174/0929867324666170516123206CrossRefPubMed

Le Rhun E, Preusser M, Roth P, Reardon DA, van den Bent M, Wen P, Reifenberger G, Weller M (2019) Molecular targeted therapy of glioblastoma. Cancer Treat Rev 80:101896. https://doi.org/10.1016/j.ctrv.2019.101896CrossRefPubMed

Palsuledesai CC, Distefano MD (2015) Protein prenylation: enzymes, therapeutics, and biotechnology applications. ACS Chem Biol 10(1):51–62. https://doi.org/10.1021/cb500791fCrossRefPubMed

Winter-Vann AM, Casey PJ (2005) Post-prenylation-processing enzymes as new targets in oncogenesis. Nat Rev Cancer 5(5):405–412. https://doi.org/10.1038/nrc1612CrossRefPubMed

Lau HY, Tang J, Casey PJ, Wang M (2017) Isoprenylcysteine carboxyl methyltransferase is critical for malignant transformation and tumor maintenance by all RAS isoforms. Oncogene 36(27):3934–3942. https://doi.org/10.1038/onc.2016.508CrossRefPubMedPubMedCentral

Chai TF, Manu KA, Casey PJ, Wang M (2020) Isoprenylcysteine carboxyl methyltransferase is required for the impact of mutant KRAS on TAZ protein level and cancer cell self-renewal. Oncogene 39(31):5373–5389. https://doi.org/10.1038/s41388-020-1364-7CrossRefPubMedPubMedCentral

Zhu Y, Hu Q, Li H (2019) Isoprenylcysteine carboxyl methyltransferase is associated with nasopharyngeal carcinoma chemoresistance and Ras activation. Biochem Biophys Res Commun 516(3):784–789. https://doi.org/10.1016/j.bbrc.2019.06.074CrossRefPubMed

Marin-Ramos NI, Balabasquer M, Ortega-Nogales FJ, Torrecillas IR, Gil-Ordonez A, Marcos-Ramiro B, Aguilar-Garrido P, Cushman I, Romero A, Medrano FJ, Gajate C, Mollinedo F, Philips MR, Campillo M, Gallardo M, Martin-Fontecha M, Lopez-Rodriguez ML, Ortega-Gutierrez S (2019) A Potent isoprenylcysteine carboxyl methyltransferase (ICMT) inhibitor improves survival in Ras-driven acute myeloid leukemia. J Med Chem 62(13):6035–6046. https://doi.org/10.1021/acs.jmedchem.9b00145CrossRefPubMed

Pan Q, Liu R, Banu H, Ma L, Li H (2018) Inhibition of isoprenylcysteine carboxyl methyltransferase sensitizes common chemotherapies in cervical cancer via ras-dependent pathway. Biomed Pharmacother 99:169–175. https://doi.org/10.1016/j.biopha.2018.01.048CrossRefPubMed

10.

Liu Q, Chen J, Fu B, Dai J, Zhao Y, Lai L (2018) Isoprenylcysteine carboxyl methyltransferase regulates ovarian cancer cell response to chemotherapy and Ras activation. Biochem Biophys Res Commun 501(2):556–562. https://doi.org/10.1016/j.bbrc.2018.05.038CrossRefPubMed

11.

Teh JT, Zhu WL, Ilkayeva OR, Li Y, Gooding J, Casey PJ, Summers SA, Newgard CB, Wang M (2015) Isoprenylcysteine carboxyl methyltransferase regulates mitochondrial respiration and cancer cell metabolism. Oncogene 34(25):3296–3304. https://doi.org/10.1038/onc.2014.260CrossRefPubMed

12.

Xu J, Zhu Y, Wang F, Zhou Y, Xia G, Xu W (2019) ICMT contributes to hepatocellular carcinoma growth, survival, migration and chemoresistance via multiple oncogenic pathways. Biochem Biophys Res Commun 518(3):584–589. https://doi.org/10.1016/j.bbrc.2019.08.094CrossRefPubMed

13.

Magkouta S, Pappas A, Moschos C, Vazakidou ME, Psarra K, Kalomenidis I (2016) Icmt inhibition exerts anti-angiogenic and anti-hyperpermeability activities impeding malignant pleural effusion. Oncotarget 7(15):20249–20259. https://doi.org/10.18632/oncotarget.7912CrossRefPubMedPubMedCentral

14.

Lau HY, Ramanujulu PM, Guo D, Yang T, Wirawan M, Casey PJ, Go ML, Wang M (2014) An improved isoprenylcysteine carboxyl methyltransferase inhibitor induces cancer cell death and attenuates tumor growth in vivo. Cancer Biol Ther 15(9):1280–1291. https://doi.org/10.4161/cbt.29692CrossRefPubMedPubMedCentral

15.

Ramanujulu PM, Yang T, Yap SQ, Wong FC, Casey PJ, Wang M, Go ML (2013) Functionalized indoleamines as potent, drug-like inhibitors of isoprenylcysteine carboxyl methyltransferase (ICMT). Eur J Med Chem 63:378–386. https://doi.org/10.1016/j.ejmech.2013.02.007S0223-5234(13)00093-7[pii]CrossRefPubMed

16.

Bergman JA, Hahne K, Song J, Hrycyna CA, Gibbs RA (2012) S-farnesyl-thiopropionic acid (FTPA) triazoles as potent inhibitors of isoprenylcysteine carboxyl methyltransferase. ACS Med Chem Lett 3(1):15–19. https://doi.org/10.1021/ml200106dCrossRefPubMed

17.

Chou TC (2010) Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res 70(2):440–446. https://doi.org/10.1158/0008-5472.CAN-09-1947CrossRefPubMed

18.

Yadav B, Wennerberg K, Aittokallio T, Tang J (2015) Searching for drug synergy in complex dose-response landscapes using an interaction potency model. Comput Struct Biotechnol J 13:504–513. https://doi.org/10.1016/j.csbj.2015.09.001CrossRefPubMedPubMedCentral

19.

Wan W, Zhang X, Huang C, Chen L, Yang X, Bao K, Peng T (2020) Monensin inhibits glioblastoma angiogenesis via targeting multiple growth factor receptor signaling. Biochem Biophys Res Commun 530(2):479–484. https://doi.org/10.1016/j.bbrc.2020.05.057CrossRefPubMed

20.

Winter-Vann AM, Baron RA, Wong W, Dela Cruz J, York JD, Gooden DM, Bergo MO, Young SG, Toone EJ, Casey PJ (2005) A small-molecule inhibitor of isoprenylcysteine carboxyl methyltransferase with antitumor activity in cancer cells. Proc Natl Acad Sci USA 102(12):4336–4341CrossRefPubMedPubMedCentral

21.

Ou A, Yung WKA, Majd N (2020) Molecular Mechanisms of Treatment resistance in glioblastoma. Int J Mol Sci. https://doi.org/10.3390/ijms22010351CrossRefPubMedPubMedCentral

22.

Kolch W (2000) Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. Biochem J 351(Pt 2):289–305CrossRefPubMedPubMedCentral

23.

Rodriguez-Viciana P, Warne PH, Dhand R, Vanhaesebroeck B, Gout I, Fry MJ, Waterfield MD, Downward J (1994) Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 370(6490):527–532. https://doi.org/10.1038/370527a0CrossRefPubMed

24.

Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z (2017) GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res 45(W1):W98–W102. https://doi.org/10.1093/nar/gkx247CrossRefPubMedPubMedCentral

25.

Borini Etichetti C, Di Benedetto C, Rossi C, Baglioni MV, Bicciato S, Del Sal G, Menacho-Marquez M, Girardini J (2019) Isoprenylcysteine carboxy methyltransferase (ICMT) is associated with tumor aggressiveness and its expression is controlled by the p53 tumor suppressor. J Biol Chem 294(13):5060–5073. https://doi.org/10.1074/jbc.RA118.006037CrossRefPubMedPubMedCentral

26.

Cushman I, Casey PJ (2009) Role of isoprenylcysteine carboxyl methyltransferase-catalyzed methylation in Rho function and migration. J Biol Chem 284(41):27964–27973. https://doi.org/10.1074/jbc.M109.025296CrossRefPubMedPubMedCentral

27.

Svilar D, Dyavaiah M, Brown AR, Tang JB, Li J, McDonald PR, Shun TY, Braganza A, Wang XH, Maniar S, St Croix CM, Lazo JS, Pollack IF, Begley TJ, Sobol RW (2012) Alkylation sensitivity screens reveal a conserved cross-species functionome. Mol Cancer Res 10(12):1580–1596. https://doi.org/10.1158/1541-7786.MCR-12-0168CrossRefPubMed

28.

Prior IA, Lewis PD, Mattos C (2012) A comprehensive survey of Ras mutations in cancer. Cancer Res 72(10):2457–2467. https://doi.org/10.1158/0008-5472.CAN-11-2612CrossRefPubMedPubMedCentral

29.

Knobbe CB, Reifenberger J, Reifenberger G (2004) Mutation analysis of the Ras pathway genes NRAS, HRAS, KRAS and BRAF in glioblastomas. Acta Neuropathol 108(6):467–470. https://doi.org/10.1007/s00401-004-0929-9CrossRefPubMed

30.

Holmen SL, Williams BO (2005) Essential role for Ras signaling in glioblastoma maintenance. Cancer Res 65(18):8250–8255. https://doi.org/10.1158/0008-5472.CAN-05-1173CrossRefPubMed

31.

Stephen AG, Esposito D, Bagni RK, McCormick F (2014) Dragging ras back in the ring. Cancer Cell 25(3):272–281. https://doi.org/10.1016/j.ccr.2014.02.017CrossRefPubMed

Title: Isoprenylcysteine carboxyl methyltransferase is critical for glioblastoma growth and survival by activating Ras/Raf/Mek/Erk
Authors: Weifeng Wan
Wenfeng Xiao
Wen Pan
Ligang Chen
Zhiyong Liu
Jianguo Xu
Publication date: 01-03-2022
Publisher: Springer Berlin Heidelberg
Keywords: Glioblastoma
Glioblastoma
Glioblastoma
Published in: Cancer Chemotherapy and Pharmacology / Issue 3/2022
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-022-04401-x

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

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 3/2022

Evaluation of cytogenetic and molecular markers with MTX-mediated toxicity in pediatric acute lymphoblastic leukemia patients

Roles of DNA polymerase ζ in the radiotherapy sensitivity and oxidative stress of lung cancer cells

Cabozantinib with or without Panitumumab for RAS wild-type metastatic colorectal cancer: impact of MET amplification on clinical outcomes and circulating biomarkers

Correlation between pharmacokinetic parameters of 5-fluorouracil and related metabolites and adverse reactions in East-Asian patients with advanced colorectal cancer

A phase I study of AZD2171 and Temsirolimus in patients with advanced gynecological malignancies

Efficacy and safety exposure–response analyses of entrectinib in patients with advanced or metastatic solid tumors

Keynote webinar | Spotlight on antibody–drug conjugates in cancer