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

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 enzy...

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Bibliographic Details
Published in:Oncogene 2015-03, Vol.34 (13), p.1718-1728
Main Authors: AbuAli, G, Chaisaklert, W, Stelloo, E, Pazarentzos, E, Hwang, M-S, Qize, D, Harding, S V, Al-Rubaish, A, Alzahrani, A J, Al-Ali, A, Sanders, T A B, Aboagye, E O, Grimm, S
Format: Article
Language:English
Subjects:
631/443/319
631/67/589/1588
631/80/82/23
631/80/86
Adenoviridae - genetics
Adenovirus
Animals
Apoptosis
Cancer
Cell Biology
Cell death
Cell proliferation
Cell Transformation, Neoplastic
Cells, Cultured
Desaturase
Development and progression
Endoplasmic Reticulum Stress
Enzymes
Fatty acids
Female
Genetic aspects
Genetic transformation
Human Genetics
Humans
Internal Medicine
Kidney cancer
Kidney Neoplasms - pathology
Kidney Neoplasms - therapy
Kidneys
Medicine
Medicine & Public Health
Metabolism
Mice
Molecular weight
Oncology
Organic Anion Transporters - genetics
Organic Anion Transporters - physiology
original-article
Properties
Protein Structure, Tertiary
Regulation
Stearoyl-CoA desaturase
Stearoyl-CoA Desaturase - physiology
Transmembrane domains
Tumor suppressor genes
Tumorigenesis
Tumors
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Summary: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.
ISSN:0950-9232
1476-5594
DOI:10.1038/onc.2014.93