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Title: ORCTL3 : insights into the function and the structure of a novel anticancer gene
Author: AbuAli, Ghada
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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ORCTL3 was recently isolated as a gene with a tumour-speci c apoptosis activity. Its transfection into transformed cells elicits an apoptosis response, while normal cells remain unaffected. In this study I show that ORCTL3 is activated for apoptosis induction by individual tumourigenic mutations in renal cells. Its activity is also shared by other so-called anticancer genes such as Mda-7/IL-24, TRAIL, Apoptin, and Par-4. This effect is independent of the tumour cells' proliferation status and is mediated by an incomplete ER stress response, characterised by ATF4, but not BiP accumulation. ATF4 upregulation and also the ARCosome, a recently discovered caspase-8-activation complex, are required for apoptosis by ORCTL3. For its effect, ORCTL3 targets the enzyme stearoyl-CoA desaturase-1 (SCD-1) that is involved in the fatty acid metabolism. This is evidenced by the inhibition of apoptosis induced through ORCTL3 when the SCD-1 product oleic acid is exogenously supplemented and by the replication of its tumour-specific effect upon chemical inhibition of SCD-1. ORCTL3's activity to specifically target tumour cells is caused by the transmembrane domains 3 and 4 of the mouse, but not the human, gene and critically depends on the expression level of the ORCTL3 protein. Finally, an adenovirus carrying the expression cassette of ORCTL3 leads to an efficient expression and therefore, substantial and specific destruction of primary renal tumour cells compared to their normal counterparts. My results indicate that ORCTL3 induces tumour-specific apoptosis by specifically targeting cancer metabolism and suggest novel therapeutic interferences for renal tumours.
Supervisor: Grimm, Stefan Sponsor: Government of Saudi Arabia
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available