NAC1 modulates sensitivity of ovarian cancer cells to cisplatin by altering the HMGB1-mediated autophagic response

Abstract

Nucleus accumbens-1 (NAC1), a nuclear factor belonging to the BTB/POZ gene family, is known to play 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 reported 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 RNAi 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-MA and chloroquine, and siRNAs targeting beclin 1 or Atg5, on the cytotoxicity of cisplatin. Treatment with 3-MA, 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 via high mobility group box1 (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.

MicroRNA-30a Sensitizes Tumor Cells to cis-Platinum via Suppressing Beclin 1-mediated Autophagy

“…Although the cytotoxicity of cis-DDP to cancer cells is not completely understood, the major mechanism underlying its antitumor activity has been ascribed to the induction of DNA damage via inducing loop structures and condensation of DNA molecules by platinum compounds (29,40). Previous studies indicated that, like many other antitumor reagents, cis-DDP treatment causes tumor cell resistance to cis-DDP (37,41). Although there are many factors that may contribute to the cis-platinum-resistance of tumor cells, increased tumor cell autophagy activity by cis-DDP treatment plays a key role in this process (37).…”

“…Previous studies indicated that, like many other antitumor reagents, cis-DDP treatment causes tumor cell resistance to cis-DDP (37,41). Although there are many factors that may contribute to the cis-platinum-resistance of tumor cells, increased tumor cell autophagy activity by cis-DDP treatment plays a key role in this process (37). Our study confirmed that cis-DDP or taxol treatment increased tumor cell autophagy, as indicated by the elevation of autophagy-related proteins beclin 1 and LC3-II, and further demonstrated that the possible mechanism underlying cis-DDP-mediated autophagic activity enhancement was the reduction of miR-30a by cis-DDP.…”

“…Heightened autophagy has been widely found in cancer cells faced with metabolic and therapeutic stress and contributes to the chemotherapy resistance of various types of tumors (37). Blocking cancer cell autophagy is emerging as a novel approach to enhance the efficiency of chemotherapy in cancer (38,39).…”

Downregulation of ATG14 by EGR1-MIR152 sensitizes ovarian cancer cells to cisplatin-induced apoptosis by inhibiting cyto-protective autophagy

“…With regards to cisplatin, recent studies demonstrated that cisplatin can induce autophagy in ovarian cancer cells through the ubiquitinbinding protein SQSTM1 or HMGB1 (high mobility group box 1). 25,26 Here, we describe a new mechanism in which downregulation of ATG14 by EGR1-MIR152 mediates cisplatin-induced autophagy in cisplatin-resistant ovarian cancer cells.…”

Chaperone-like Activity of High-Mobility Group Box 1 Protein and Its Role in Reducing the Formation of Polyglutamine Aggregates

“…Extracellular HMGB1 functions as a proinflammatory cytokine-like molecule by direct binding to TLR4 or indirectly binding with other molecules (41). In addition, HMGB1 can play an intracytoplasmic role as a regulator between macroautophagy and apoptosis (11,(42)(43)(44) and a sentinel molecule for viral nucleic acid sensing (45).…”