Exogenous p53 and ASPP2 expression enhances rAdV-TK/ GCV-induced death in hepatocellular carcinoma cells lacking...

Area of Science:

• Oncology
• Gene Therapy
• Molecular Biology

Background:

• Suicide gene therapy utilizing herpes simplex virus-1 thymidine kinase (HSV-TK) with ganciclovir (GCV) is a potential cancer treatment.
• The efficacy of HSV-TK/GCV therapy in hepatocellular carcinoma (HCC) may be influenced by the p53 tumor suppressor gene's status.

Purpose of the Study:

• To investigate the role of p53 status in the efficacy of HSV-TK/GCV suicide gene therapy for hepatocellular carcinoma (HCC).
• To explore the combined effects of overexpressing p53 and ASPP2 with HSV-TK/GCV therapy in HCC cells.

Main Methods:

• Overexpression of thymidine kinase (TK), p53, and ASPP2 using recombinant adenoviral vectors (rAdV) in HCC cell lines (Hep3B, HepG2) and primary HCC cells.
• Assessment of cell viability and molecular markers (γ-H2AX, p-ATM, Bax, p21) following rAdV-TK/GCV treatment in cells with varying p53 and ASPP2 expression.

Main Results:

• p53 overexpression induced cell death in p53-null Hep3B cells but not in wild-type p53 HepG2 cells.
• ASPP2 overexpression enhanced rAdV-TK/GCV-induced cell death in HepG2 cells by interacting with wild-type p53, but not with mutated p53 (R249S).
• Increased expression of DNA damage markers (γ-H2AX, p-ATM) and apoptosis-related proteins (Bax, p21) was observed in HepG2 cells treated with rAdV-TK/GCV.

Conclusions:

• The efficacy of HSV-TK/GCV suicide gene therapy in HCC is significantly influenced by the p53 tumor suppressor gene's status.
• Co-expression of ASPP2 with HSV-TK/GCV can enhance therapeutic effects in HCC cells with wild-type p53, suggesting a synergistic mechanism.
• Combined gene therapy involving HSV-TK, GCV, p53, and ASPP2 warrants further investigation for improved HCC treatment, particularly in patients with non-functional p53.