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The anticancer gene ORCTL3 targets stearoyl-CoA desaturase-1 for tumour-specific apoptosis

Oncogene volume 34, pages 1718–1728 (2015)Cite this article

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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.

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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.

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Author notes

  1. A J Alzahrani

    Present address: 5Current address: King Saud University, Department of Clinical Laboratories Sciences, College of Applied Medical Sciences, Riyadh 11663, Saudi Arabia.,

Authors and Affiliations

  1. Division of Experimental Medicine, Imperial College London, Hammersmith Campus, London, UK

    G AbuAli, W Chaisaklert, E Stelloo, E Pazarentzos, M-S Hwang, D Qize & S Grimm

  2. Diabetes & Nutritional Sciences Division, King's College London, London, UK

    S V Harding & T A B Sanders

  3. Prince Mohammed Center for Research & Consultation Studies, College of Medicine, University of Dammam, Dammam, Kingdom of Saudi Arabia

    A Al-Rubaish, A J Alzahrani & A Al-Ali

  4. Division of Cancer, Imperial College London, Hammersmith Campus, London, UK

    E O Aboagye

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Correspondence to S Grimm.

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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

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