Abstract
ORCTL3 is a member of a group of genes, the so-called anticancer genes, that cause tumour-specific cell death. We show that this activity is triggered in isogenic renal cells upon their transformation independently of the cells’ proliferation status. For its cell death effect ORCTL3 targets the enzyme stearoyl-CoA desaturase-1 (SCD1) in fatty acid metabolism. This is caused by transmembrane domains 3 and 4, which are more efficacious in vitro than a low molecular weight drug against SCD1, and critically depend on their expression level. SCD1 is found upregulated upon renal cell transformation indicating that its activity, while not impacting proliferation, represents a critical bottleneck for tumourigenesis. An adenovirus expressing ORCTL3 leads to growth inhibition of renal tumours in vivo and to substantial destruction of patients’ kidney tumour cells ex vivo. Our results indicate fatty acid metabolism as a target for tumour-specific apoptosis in renal tumours and suggest ORCTL3 as a means to accomplish this.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Danen-Van Oorschot AA, Fischer DF, Grimbergen JM, Klein B, Zhuang S, Falkenburg JH et al. Apoptin induces apoptosis in human transformed and malignant cells but not in normal cells. Proc Natl Acad Sci USA 1997; 94: 5843–5847.
Su ZZ, Madireddi MT, Lin JJ, Young CS, Kitada S, Reed JC et al. The cancer growth suppressor gene mda-7 selectively induces apoptosis in human breast cancer cells and inhibits tumor growth in nude mice. Proc Natl Acad Sci USA 1998; 95: 14400–14405.
Meter Van, Mao M, Gorbunova Z, Seluanov V . SIRT6 A overexpression induces massive apoptosis in cancer cells but not in normal cells. Cell Cycle 2011; 10: 3153–3158.
Nalca A, Qiu SG, El-Guendy N, Krishnan S, Rangnekar VM . Oncogenic Ras sensitizes cells to apoptosis by Par-4. J Biol Chem 1999; 274: 29976–29983.
Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 1995; 3: 673–682.
Grimm S, Noteborn M . Anticancer genes: inducers of tumour-specific cell death signalling. Trends Mol Med 2010; 16: 88–96.
Irshad S, Mahul-Mellier AL, Kassouf N, Lemarie A, Grimm S . Isolation of ORCTL3 in a novel genetic screen for tumor-specific apoptosis inducers. Cell Death Differ 2009; 16: 890–898.
Kroemer G, Pouyssegur J . Tumor cell metabolism: cancer's Achilles' heel. Cancer Cell 2008; 13: 472–482.
Cheong H, Lu C, Lindsten T, Thompson CB . Therapeutic targets in cancer cell metabolism and autophagy. Nat Biotechnol 2012; 30: 671–678.
Hsu PP, Sabatini DM . Cancer cell metabolism: Warburg and beyond. Cell 2008; 134: 703–707.
Linehan WM, Yang JC, Rini B . Cancer of the kidney. In: DeVita VTea (ed.). Cancer: Principles and Practice of Oncology, vol. 4. Lippincott Williams & Wilkins: New Haven, CT, 2011 pp 1161–1182.
Singer EA, Gupta GN, Srinivasan R . Update on targeted therapies for clear cell renal cell carcinoma. Curr Opin Oncol 2011; 23: 283–289.
Jensen FC, Girardi AJ, Gilden RV, Koprowski H . Infection of human and simian tissue cultures with rous sarcoma virus. Proc Natl Acad Sci USA 1964; 52: 53–59.
Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012; 366: 883–892.
Dalgliesh GL, Furge K, Greenman C, Chen L, Bignell G, Butler A et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 2010; 463: 360–363.
Fujita J, Kraus MH, Onoue H, Srivastava SK, Ebi Y, Kitamura Y et al. Activated H-ras oncogenes in human kidney tumors. Cancer Res 1988; 48: 5251–5255.
Gordan JD, Lal P, Dondeti VR, Letrero R, Parekh KN, Oquendo CE et al. HIF-alpha effects on c-Myc distinguish two subtypes of sporadic VHL-deficient clear cell renal carcinoma. Cancer Cell 2008; 14: 435–446.
Noon AP, Vlatkovic N, Polanski R, Maguire M, Shawki H, Parsons K et al. p53 and MDM2 in renal cell carcinoma: biomarkers for disease progression and future therapeutic targets? Cancer 2010; 116: 780–790.
Nevels M, Dobner T . Determination of the transforming activities of adenovirus oncogenes. Methods Mol Med 2007; 131: 187–195.
Navin N, Kendall J, Troge J, Andrews P, Rodgers L, McIndoo J et al. Tumour evolution inferred by single-cell sequencing. Nature 2011; 472: 90–94.
Khwaja A, Rodriguez-Viciana P, Wennstrom S, Warne PH, Downward J . Matrix adhesion and Ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/Akt cellular survival pathway. EMBO J 1997; 16: 2783–2793.
Iwasawa R, Mahul-Mellier AL, Datler C, Pazarentzos E, Grimm S . Fis1 and Bap31 bridge the mitochondria-ER interface to establish a platform for apoptosis induction. EMBO J 2011; 30: 556–568.
Morgan-Lappe SE, Tucker LA, Huang X, Zhang Q, Sarthy AV, Zakula D et al. Identification of Ras-related nuclear protein, targeting protein for xenopus kinesin-like protein 2, and stearoyl-CoA desaturase 1 as promising cancer targets from an RNAi-based screen. Cancer Res 2007; 67: 4390–4398.
Minville-Walz M, Pierre AS, Pichon L, Bellenger S, Fevre C, Bellenger J et al. Inhibition of stearoyl-CoA desaturase 1 expression induces CHOP-dependent cell death in human cancer cells. PLoS ONE 2010; 5: e14363.
Wessels HP, Spiess M . Insertion of a multispanning membrane protein occurs sequentially and requires only one signal sequence. Cell 1988; 55: 61–70.
Valente MJ, Henrique R, Costa VL, Jeronimo C, Carvalho F, Bastos ML et al. A rapid and simple procedure for the establishment of human normal and cancer renal primary cell cultures from surgical specimens. PLoS ONE 2011; 6: e19337.
Burikhanov R, Zhao Y, Goswami A, Qiu S, Schwarze SR, Rangnekar VM . The tumor suppressor Par-4 activates an extrinsic pathway for apoptosis. Cell 2009; 138: 377–388.
Rohn JL, Zhang YH, Aalbers RI, Otto N, Den Hertog J, Henriquez NV et al. A tumor-specific kinase activity regulates the viral death protein Apoptin. J Biol Chem 2002; 277: 50820–50827.
Zeisig R, Koklic T, Wiesner B, Fichtner I, Sentjurc M . Increase in fluidity in the membrane of MT3 breast cancer cells correlates with enhanced cell adhesion in vitro and increased lung metastasis in NOD/SCID mice. Arch Biochem Biophys 2007; 459: 98–106.
Funaki NO, Tanaka J, Kohmoto M, Sugiyama T, Ohshio G, Nonaka A et al. Membrane fluidity correlates with liver cancer cell proliferation and infiltration potential. Oncol Rep 2001; 8: 527–532.
Brown JM, Rudel LL . Stearoyl-coenzyme A desaturase 1 inhibition and the metabolic syndrome: considerations for future drug discovery. Curr Opin Lipidol 2010; 21: 192–197.
Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ . Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 2003; 348: 1625–1638.
Ceschi M, Gutzwiller F, Moch H, Eichholzer M, Probst-Hensch NM . Epidemiology and pathophysiology of obesity as cause of cancer. Swiss Med Wkly 2007; 137: 50–56.
Gong Z, Agalliu I, Lin DW, Stanford JL, Kristal AR . Obesity is associated with increased risks of prostate cancer metastasis and death after initial cancer diagnosis in middle-aged men. Cancer 2007; 109: 1192–1202.
Igal RA . Stearoyl-CoA desaturase-1: a novel key player in the mechanisms of cell proliferation, programmed cell death and transformation to cancer. Carcinogenesis 2010; 31: 1509–1515.
Muthana M, Rodrigues S, Chen YY, Welford A, Hughes R, Tazzyman S et al. Macrophage delivery of an oncolytic virus abolishes tumor regrowth and metastasis after chemotherapy or Irradiation. Cancer Res 2012; 73: 490–495.
Mahul-Mellier AL, Pazarentzos E, Datler C, Iwasawa R, Abuali G, Lin B et al. De-ubiquitinating protease USP2a targets RIP1 and TRAF2 to mediate cell death by TNF. Cell Death Differ 2011; 19: 891–899.
Lepage G, Roy CC . Direct transesterification of all classes of lipids in a one-step reaction. J Lipid Res 1986; 27: 114–120.
Acknowledgements
GA was supported by the Ministry of Higher Education in Saudi Arabia. EP was supported by the Cancer Research UK, WC by the Development and Promotion of Science and Technology Talents Project (DPST), Royal Thai Government, Thailand and MSH by a stipend from AstraZeneca Ltd. We thank Joel Abraham for in vivo work and the Imperial’s tissue bank, Dr David Hrouda, Ms Taneisha McFarlane, and Prof Gerry Thomas, for help. Tissue samples were provided by the Imperial College Healthcare NHS Trust Tissue Bank. Other investigators may have received samples from these same tissues. The research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. We thank Mr Robert Gray for lipid extraction and primary GC analysis.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies this paper on the Oncogene website
Supplementary information
Rights and permissions
About this article
Cite this article
AbuAli, G., Chaisaklert, W., Stelloo, E. et al. The anticancer gene ORCTL3 targets stearoyl-CoA desaturase-1 for tumour-specific apoptosis. Oncogene 34, 1718–1728 (2015). https://doi.org/10.1038/onc.2014.93
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2014.93
This article is cited by
-
Genetic screening for anticancer genes highlights FBLN5 as a synthetic lethal partner of MYC
Cell Communication and Signaling (2023)
-
Expression profiling of anticancer genes in colorectal cancer patients and their in vitro induction by riproximin, a ribosomal inactivating plant protein
Journal of Cancer Research and Clinical Oncology (2022)
-
Lung fibroblasts promote metastatic colonization through upregulation of stearoyl-CoA desaturase 1 in tumor cells
Oncogene (2018)