Translocation of catalase and SODs protects from doxorubicin‐induced nuclear damage in cultured human ovarian cancer cells (554.2)

Abstract

Doxorubicin is applied clinically to treat ovarian cancer, and yet the molecular mode of actions of doxorubicin is far from clear. Our most recent study has shown that antioxidant N‐acetylcysteine (NAC) potentiates doxorubicin‐induced activation of p53 and ATM, suggesting that endogenous antioxidant enzymes may play important roles in the response of ovarian cancer cells to doxorubicin treatment. In this study, we investigated the expression of catalase and SOD1, 2 and 3 in cultured ovarian cancer cells (CaOV3). Western blot data showed that CaOV3 cells express catalase and SOD1, 2, and 3. Serum starvation reduces expression of those enzymes, while EGF treatment induces EGFR and mTOR activation and the expression of those enzymes. mTOR inhibitor, Rapamycin, PI3K/AKT inhibitor LY294002, and MEK/ERK inhibitor U0126 inhibit expression. Interestingly, doxorubicin treatment induces translocation of those enzymes from cytoplasm to nucleus in a dose and time dependent manner, however, chemo drug paclitaxel has no such effect. Our data suggest that to avoid widespread oxidative stress and nuclear damage, ovarian cancer cells protect themselves via translocation of the antioxidant enzymes in response to doxorubicin treatment. Thus, inhibition of such translocation may enhance the efficacy of doxorubicin in vivo. Collectively, our data support the notion that combo treatment with inhibitors of mTOR and MEK/ERK pathways and doxorubicin may yield better clinical outcome.Grant Funding Source: Rhode Island INBRE