Myoferlin; Mitochondria; DNA damage; p53; OXPHOS; metabolism
Résumé :
[en] Colon adenocarcinoma is the third most commonly diagnosed cancer and the second deadliest one. Metabolic reprogramming, described as an emerging hallmark of malignant cells, includes the predominant use of glycolysis to produce energy. Recent studies demonstrated that mitochondrial electron transport chain inhibitor reduced colon cancer tumour growth. Accumulating evidence show that myoferlin, a member of the ferlin family, is highly expressed in several cancer types, where it acts as a tumour-promoter and participates in the metabolic rewiring towards oxidative metabolism. In this study, we showed that myoferlin expression in colon cancer lesions is associated with low patient survival and is higher than in non-tumoural adjacent tissue. Human colon cancer cells silenced for myoferlin exhibit a reduced oxidative phosphorylation activity associated with mitochondrial fission leading, ROS accumulation, decreased cell growth, and increased apoptosis. We observed the triggering of a DNA damage response culminating to a cell cycle arrest in wild-type p53 cells. The use of a p53 null cell line or a compound able to restore p53 activity (Prima-1) reverted the effects induced by myoferlin silencing, confirming the involvement of p53. The recent identification of a compound interacting with a myoferlin C2 domain and bearing anti-cancer potency identifies, together with our demonstration, this protein as a suitable new therapeutic target in colon cancer.
Bellier, Justine ; Université de Liège - ULiège > Cancer-Metastases Research Laboratory
Herfs, Michael ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques
Peiffer, Raphaël ; Université de Liège - ULiège > Master sc. bioméd., à fin.
Agirman, Ferman ; Université de Liège - ULiège > Cancer-Metastases Research Laboratory
Maloujahmoum, Naïma ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Département des sciences biomédicales et précliniques
Habraken, Yvette ; Université de Liège - ULiège > Molecular Biology of Diseases-Gene Expression & Cancer
Delvenne, Philippe ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques
Bellahcene, Akeila ; Université de Liège - ULiège > Cancer-Metastases Research Laboratory
Castronovo, Vincenzo ✱; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie générale et cellulaire
Peulen, Olivier ✱; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Département des sciences biomédicales et précliniques
✱ Ces auteurs ont contribué de façon équivalente à la publication.
Langue du document :
Anglais
Titre :
Human colon cancer cells highly express myoferlin to maintain a fit mitochondrial network and escape p53-driven apoptosis.
Date de publication/diffusion :
2019
Titre du périodique :
Oncogenesis
ISSN :
2157-9024
Maison d'édition :
Nature Publishing Group, Etats-Unis
Peer reviewed :
Peer reviewed vérifié par ORBi
Organisme subsidiant :
Fonds Léon Fredericq [BE] F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE]
Siegel, R. L. et al. Colorectal cancer statistics, 2017. CA Cancer J. Clin. 67, 177–193 (2017).
Bray, F. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 10.3322/caac.21492 (2018).
Koppenol, W. H., Bounds, P. L. & Dang, C. V. Otto Warburg's contributions to current concepts of cancer metabolism. Nat. Rev. Cancer 11, 325–337 (2011).
Vellinga, T. T. et al. SIRT1/PGC1a-dependent increase in oxidative phosphorylation supports chemotherapy resistance of colon cancer. Clin. Cancer Res. 21, 2870–2879 (2015).
Denise, C. et al. 5-Fluorouracil resistant colon cancer cells are addicted to OXPHOS to survive and enhance stem-like traits. Oncotarget 6, 41706–41721 (2015).
Lin, C.-S. et al. Role of mitochondrial function in the invasiveness of human colon cancer cells. Oncol. Rep. 39, 316–330 (2018).
Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Weinberg, S. E. & Chandel, N. S. Targeting mitochondria metabolism for cancer therapy. Nat. Chem. Biol. 11, 9–15 (2015).
Zhang, X. et al. Induction of mitochondrial dysfunction as a strategy for targeting tumour cells in metabolically compromised microenvironments. Nat. Commun. 5, 3295 (2014).
Doherty, K. R. et al. Normal myoblast fusion requires myoferlin. Development 132, 5565–5575 (2005).
Doherty, K. R. et al. The endocytic recycling protein EHD2 interacts with myoferlin to regulate myoblast fusion. J. Biol. Chem. 283, 20252–20260 (2008).
Turtoi, A. et al. Identification of novel accessible proteins bearing diagnostic and therapeutic potential in human pancreatic ductal adenocarcinoma. J. Proteome Res. 10, 4302–4313 (2011).
Turtoi, A. et al. Myoferlin is a key regulator of EGFR activity in breast cancer. Cancer Res. 73, 5438–5448 (2013).
Fahmy, K. et al. Myoferlin plays a key role in VEGFA secretion and impacts tumor-associated angiogenesis in human pancreas cancer. Int. J. Cancer 138, 652–663 (2016).
Blomme, A. et al. Myoferlin is a novel exosomal protein and functional regulator of cancer-derived exosomes. Oncotarget 7, 83669–83683 (2016).
Blomme, A. et al. Myoferlin regulates cellular lipid metabolism and promotes metastases in triple-negative breast cancer. Oncogene 4, 1151 (2016).
Rademaker, G. et al. Myoferlin controls mitochondrial structure and activity in pancreatic ductal adenocarcinoma, and affects tumor aggressiveness. Oncogene 66, 1–15 (2018).
Mizuno, H., Kitada, K., Nakai, K. & Sarai, A. PrognoScan: a new database for meta-analysis of the prognostic value of genes. BMC Med. Genomics 2, 18 (2009).
Anaya, J. OncoLnc : Linking TCGA survival data to mRNAs, miRNAs, and lncRNAs. PeerJ Comput. Sci. 2, e67 (2016).
Song, D. H. et al. Prognostic role of myoferlin expression in patients with clear cell renal cell carcinoma. Oncotarget 8, 89033–89039 (2017).
Hoppins, S., Lackner, L. & Nunnari, J. The machines that divide and fuse mitochondria. Annu. Rev. Biochem. 76, 751–780 (2007).
Liu, Y. & Kulesz-Martin, M. p53 protein at the hub of cellular DNA damage response pathways through sequence-specific and non-sequence-specific DNA binding. Carcinogenesis 22, 851–860 (2001).
Buschmann, T. et al. Jun NH2-terminal kinase phosphorylation of p53 on Thr-81 is important for p53 stabilization and transcriptional activities in response to stress. Mol. Cell. Biol. 21, 2743–2754 (2001).
Minamoto, T. et al. Distinct pattern of p53 phosphorylation in human tumors. Oncogene 20, 3341–3347 (2001).
Ippolito, L. et al. Metabolic shift toward oxidative phosphorylation in docetaxel resistant prostate cancer cells. Oncotarget 7, 61890–61904 (2016).
Haq, R. et al. Oncogenic BRAF regulates oxidative metabolism via PGC1α and MITF. Cancer Cell 23, 302–315 (2013).
Viale, A. et al. Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature 514, 628–632 (2014).
Boudreau, A. et al. Metabolic plasticity underpins innate and acquired resistance to LDHA inhibition. Nat. Chem. Biol. 12, 779–786 (2016).
Fryknäs, M. et al. Iron chelators target both proliferating and quiescent cancer cells. Sci. Rep. 6, 38343 (2016).
Vitiello, G. A. et al. Mitochondrial inhibition augments the efficacy of imatinib by resetting the metabolic phenotype of gastrointestinal stromal tumor. Clin. Cancer Res. 24, 972–984 (2018).
Amatschek, S. et al. Tissue-wide expression profiling using cDNA subtraction and microarrays to identify tumor-specific genes. Cancer Res. 64, 844–856 (2004).
McKinney, K. Q. et al. Discovery of putative pancreatic cancer biomarkers using subcellular proteomics. J. Proteomics 74, 79–88 (2011).
Wang, W. S. et al. ITRAQ-based quantitative proteomics reveals myoferlin as a novel prognostic predictor in pancreatic adenocarcinoma. J. Proteomics 91, 453–465 (2013).
Kumar, B. et al. High expression of myoferlin is associated with poor outcome in oropharyngeal squamous cell carcinoma patients and is inversely associated with HPV-status. Oncotarget 7, 18665–18677 (2016).
Kim, M. H. et al. Myoferlin expression and its correlation with FIGO histologic grading in early-stage endometrioid carcinoma. J. Pathol. Transl. Med. 52, 93–97 (2018).
Song, D. H. et al. Myoferlin expression in non-small cell lung cancer: Prognostic role and correlation with VEGFR-2 expression. Oncol. Lett. 11, 998–1006 (2016).
Yadav, A., Kumar, B., Lang, J. C., Teknos, T. N. & Kumar, P. A muscle-specific protein ‘myoferlin’ modulates IL-6/STAT3 signaling by chaperoning activated STAT3 to nucleus. Oncogene 36, 6374–6382 (2017).
Corvinus, F. M. et al. Persistent STAT3 activation in colon cancer is associated with enhanced cell proliferation and tumor growth. Neoplasia 7, 545–555 (2005).
Park, J. H. et al. Signal transduction and activator of transcription-3 (STAT3) in patients with colorectal cancer: associations with the phenotypic features of the tumor and host. Clin. Cancer Res. 23, 1698–1709 (2017).
Ji, H. et al. Proteome profiling of exosomes derived from human primary and metastatic colorectal cancer cells reveal differential expression of key metastatic factors and signal transduction components. Proteomics 13, 1672–1686 (2013).
Kashatus, J. A. et al. Erk2 phosphorylation of Drp1 promotes mitochondrial fission and MAPK-driven tumor growth. Mol. Cell 57, 537–551 (2015).
Hermanns, C. et al. The novel MKL target gene myoferlin modulates expansion and senescence of hepatocellular carcinoma. Oncogene 36, 3464–3476 (2017).
Piper, A.-K. et al. Enzymatic cleavage of myoferlin releases a dual C2-domain module linked to ERK signalling. Cell. Signal. 33, 30–40 (2017).
Hamelin, R. et al. Association of p53 mutations with short survival in colorectal cancer. Gastroenterology 106, 42–48 (1994).
Li, A.-J. et al. PIK3CA and TP53 mutations predict overall survival of stage II/III colorectal cancer patients. World J. Gastroenterol. 24, 631–640 (2018).
Warren, R. S. et al. Association of TP53 mutational status and gender with survival after adjuvant treatment for stage III colon cancer: results of CALGB 89803. Clin. Cancer Res. 19, 5777–5787 (2013).
Li, X.-L. et al. PRIMA-1met (APR-246) inhibits growth of colorectal cancer cells with different p53 status through distinct mechanisms. Oncotarget 6, 36689–36699 (2015).
Lu, T. et al. PRIMA-1Met suppresses colorectal cancer independent of p53 by targeting MEK. Oncotarget 7, 83017–83030 (2016).
Bykov, V. J. N., Lambert, J. M. R., Hainaut, P. & Wiman, K. G. Mutant p53 rescue and modulation of p53 redox state. Cell Cycle 8, 2509–2517 (2009).
Ježek, J., Cooper, K. F. & Strich, R. Reactive oxygen species and mitochondrial dynamics: the yin and yang of mitochondrial dysfunction and cancer progression. Antioxidants (Basel) 7, E13 (2018).
Macip, S. et al. Influence of induced reactive oxygen species in p53-mediated cell fate decisions. Mol. Cell. Biol. 23, 8576–8585 (2003).
Nicolaes, G. A. F. et al. Rational design of small molecules targeting the C2 domain of coagulation factor VIII. Blood 123, 113–120 (2014).
Zhang, T. et al. A small molecule targeting myoferlin exerts promising anti-tumor effects on breast cancer. Nat. Commun. 9, 3726 (2018).
Peixoto, P. et al. HDAC5 is required for maintenance of pericentric heterochromatin, and controls cell-cycle progression and survival of human cancer cells. Cell Death Differ. 19, 1239–1252 (2012).
Valente, A. J., Maddalena, L. A., Robb, E. L., Moradi, F. & Stuart, J. A. A simple ImageJ macro tool for analyzing mitochondrial network morphology in mammalian cell culture. Acta Histochem. 119, 315–326 (2017).
Peulen, O. J. et al. The anti-tumor effect of HDAC inhibition in a human pancreas cancer model is significantly improved by the simultaneous inhibition of cyclooxygenase 2. PLoS ONE 8, e75102 (2013).
R Development Core Team. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing: Vienna, Austria (2014). http://www.R-project.org/.