Nucleus accumbens-1 (NAC1), a nuclear factor belonging to the BTB/POZ gene family, is known to have important roles in proliferation and growth of
tumor cells and in
chemotherapy resistance. Yet, the mechanisms underlying how NAC1 contributes to drug resistance remain largely unclear. We report here that autophagy was involved in NAC1-mediated resistance to
cisplatin, a commonly used chemotherapeutic
drug in the treatment of
ovarian cancer. We found that treatment with
cisplatin caused an activation of autophagy in
ovarian cancer cell lines, A2780, OVCAR3 and SKOV3. We further demonstrated that knockdown of NAC1 by RNA interference or inactivation of NAC1 by inducing the expression of a NAC1 deletion mutant that contains only the BTB/POZ domain significantly inhibited the
cisplatin-induced autophagy, resulting in increased
cisplatin cytotoxicity. Moreover, inhibition of autophagy and sensitization to
cisplatin by NAC1 knockdown or inactivation were accompanied by induction of apoptosis. To confirm that the sensitizing effect of NAC1 inhibition on the cytotoxicity of
cisplatin was attributed to suppression of autophagy, we assessed the effects of the autophagy inhibitors
3-methyladenosine and
chloroquine, and small interfering RNAs (siRNAs) targeting
beclin 1 or Atg5 on the cytotoxicity of
cisplatin. Treatment with
3-methyladenosine,
chloroquine or
beclin 1 and Atg5-targeted
siRNA also enhanced the sensitivity of SKOV3, A2780 and OVCAR3 cells to
cisplatin, indicating that suppression of autophagy indeed renders
tumor cells more sensitive to
cisplatin. Regulation of autophagy by NAC1 was mediated by the high-mobility group box 1 (
HMGB1), as the functional status of NAC1 was associated with the expression, translocation and release of
HMGB1. The results of our study not only revealed a new mechanism determining
cisplatin sensitivity but also identified NAC1 as a novel regulator of autophagy. Thus, the NAC1-mediated autophagy may be exploited as a new target for enhancing the efficacy of
cisplatin against
ovarian cancer and other types of
malignancies.