Synergic CSE1L/CAS, TNFR-1, and p53 apoptotic pathways in combined interferon-γ/adriamycin-induced apoptosis of Hep G2 hepatoma cells

Many cancers are chemotherapy-resistant. Chemotherapy combined with immunotherapy offers a potential avenue for the treatment of chemotherapy-resistant cancers. In this study, we investigated the apoptotic pathways induced by combined interferon-γ/adriamycin treatment in Hep G2 cells. Our data showed that Hep G2 cells treated with combined interferon-γ/adriamycin enhanced cell apoptosis in comparison with that of cells treated with adriamycin. Interferon-γ increased TNFR-1, CSE1L/CAS (cellular apoptosis susceptibility protein), Bax, and Bad levels. Adriamycin increased p53 and Bax, but not TNFR-1 and CAS levels. Interferon-γ did not increase p53 accumulation; nevertheless it enhanced adriamycin-induced p53 accumulation. Overexpression of IRF-1 augmented the combined interferon-γ/adriamycin-induced p53 accumulation. Interferon-γ co-treatment increased the stability of p53 protein induced by adriamycin. Our data suggest that TNF-γ may greatly enhance the combined interferon-γ/chemotherapeutic drug-induced apoptosis of cancers. Our findings also indicate that CAS, TN-FR-1, p53, Bax, and Bad may be the targets for the interferon-γ-based chemo-immunotherapy of the chemotherapy- resistant cancers.