Role of Oxidative Stress-triggered Redox Adaptation Mechanism and Genetically Endowed Expression Profile of Antioxidant Enzymes in the modulation of Intrinsic and Acquired Chemoand Radio-resistance of Human Hepatocellular Carcinoma Cells

Using a panel of five hepatocellular carcinoma cells (HCCs) exhibiting varying degrees of intracellular oxidative stress status (IOSS) as the experiment cell model, we formulate this three-year research proposal in order to address the following specific aims: (1) Insight into the possible mechanism(s) associated with folate deficiency-induced redox adaptation response that confers chemo- and radio-resistance in a highly oxidative-stressed hepatoma subline SK-Hep-1 cells. (2) To identify the genetically endowed radioresistance-associated molecular signatures in an established radioresistant HCC Mahlavu cells and to shed some lights into the mechanistic pathways that are involved in regulating the expression of these radioresistant effectors (Bcl-2, surviving and GRP-78). Are cisplatin-induced radiosensitization during concomitant radiation therapy (CRT) proceeded via the suppression of the pathways regulating the expression of Bcl-2, survivin and GRP-78 ? (3) To obtain evidence to substantiate that survivin-instigated chemo-and radio-resistance in HCCs involves dual functional attributes: (1) effective upregulation of antioxidant enzymes and serves as a ROS sinker. (ii) Positive regulation of HIF-2α/Oct 4/c-Myc triangular circuit that controls cellular proliferation. (4) To obtain definitive evidence to substantiate that γ-Glutamylcysteine synthetase heavy chain (γ-GCSh) as a target for overcoming chemo- and radio-resistance in HCC cells. (5) Elucidating the role of genetically endowed expression profile of antioxidant enzymes in the acquisition of chemo- and radio-resistant phenotype of HCC cells.