Isolation and characterization of the anticancer gene organic cation transporter like-3 (ORCTL3).

ORCTL3, an organic cation/anion transporter expressed in various tissue types, was isolated in a genome-wide cDNA screen as a gene with a tumor-specific apoptosis activity. When overexpressed it elicits an apoptosis response in many transformed cells, while normal cells remain unaffected. It can be activated for apoptosis induction by individual tumorigenic mutations in renal cells. This effect is independent of the tumor cells' proliferation status and mediated by an incomplete ER stress response, characterized by the accumulation of the endoplasmic reticulum-stress marker ATF4, but not BiP. Recent studies show that for its apoptosis induction activity 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 or when SCD-1 is co-transfected in the transformed cells. ORCTL3's activity to specifically target tumor cells is caused by the transmembrane domains 3 and 4 of the mouse, but not the human, gene. In an in vivo model ORCTL3 shows a significant shrinkage in the size of xenograft tumors when injected with an adenoviral carrier carrying the mouse ORCTL3 gene. An ex vivo study using human renal cancer cells confirmed the promising tumor-specific apoptosis effect of ORCTL3. Since ORCTL3 targets fatty acid metabolism in transformed cells and induces an ER stress specifically in these cells, it reveals a novel therapeutic interference option for tumor cells.