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 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.
Division of Experimental Medicine, Imperial College London, Hammersmith Campus, London, UK.
G
G
AbuAli
Division of Experimental Medicine, Imperial College London, Hammersmith Campus, London, UK.
W
W
Chaisaklert
Division of Experimental Medicine, Imperial College London, Hammersmith Campus, London, UK.
E
E
Stelloo
Division of Experimental Medicine, Imperial College London, Hammersmith Campus, London, UK.
E
E
Pazarentzos
Division of Experimental Medicine, Imperial College London, Hammersmith Campus, London, UK.
M-S
MS
Hwang
Division of Experimental Medicine, Imperial College London, Hammersmith Campus, London, UK.
D
D
Qize
Diabetes & Nutritional Sciences Division, King's College London, London, UK.
S V
SV
Harding
Prince Mohammed Center for Research & Consultation Studies, College of Medicine, University of Dammam, Dammam, Kingdom of Saudi Arabia.
A
A
Al-Rubaish
Prince Mohammed Center for Research & Consultation Studies, College of Medicine, University of Dammam, Dammam, Kingdom of Saudi Arabia.
A J
AJ
Alzahrani
Prince Mohammed Center for Research & Consultation Studies, College of Medicine, University of Dammam, Dammam, Kingdom of Saudi Arabia.
A
A
Al-Ali
Diabetes & Nutritional Sciences Division, King's College London, London, UK.
T A B
TA
Sanders
Division of Cancer, Imperial College London, Hammersmith Campus, London, UK.
E O
EO
Aboagye
Division of Experimental Medicine, Imperial College London, Hammersmith Campus, London, UK.
S
S
Grimm
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000473:pathology / Q000628:therapy*; D051379:Mice; D027361:Organic Anion Transporters / Q000235:genetics* / Q000502:physiology; D017434:Protein Structure, Tertiary; D013230:Stearoyl-CoA Desaturase / Q000502:physiology*
D027361:Organic Anion Transporters; C530205:SLC22A13 protein, human; C523776:SCD1 protein, human; D013230:Stearoyl-CoA Desaturase