Abstract 4429: EGR1-MIR152 pathway overcomes acquired cisplatin resistance in ovarian cancer cells by inhibiting cyto-protective autophagy via ATG14

Abstract

Abstract The cytotoxic-based platinum compound cisplatin has been commonly used in ovarian cancer treatment for almost three decades. However, the intrinsic and acquired resistance to cisplatin in cancer cells remains a big challenge for overall survival. A growing body of evidence indicates a role of autophagy as a prosurvival and resistance mechanism against chemotherapy. Here, we reported MIR152 as a new autophagy-regulating miRNA that plays a role in cisplatin resistance. We showed that MIR152 expression was dramatically downregulated in the cisplatin-resistant cell lines A2780/CP70, SKOV3/DDP compared with their respective parental cells, and in ovarian cancer tissues associated with cisplatin resistance. Overexpression of MIR152 sensitized cisplatin-resistant ovarian cancer cells by reducing cisplatin-induced autophagy, enhancing cisplatin-induced apoptosis and inhibition of cell proliferation. A mouse subcutaneous xenograft tumor model using A2780/CP70 cells with overexpressing MIR152 was established and displayed decreased tumor growth in response to cisplatin. We also identified that ATG14 is a functional target of MIR152 in regulating autophagy inhibition. Furthermore, we found that EGR1 (early growth response 1) regulated the MIR152 gene at the transcriptional level. Ectopic expression of EGR1 enhanced efficacy of chemotherapy in A2780/CP70 cells. More importantly, these findings were relevant to clinical cases. Both EGR1 and MIR152 expression levels were significantly lower in human ovarian cancer tissues with high levels of ERCC1 (excision repair cross-complementation group 1), a marker for cisplatin resistance. Collectively, these data provide insights into novel mechanisms for acquired cisplatin resistance. Activation of EGR1 and MIR152 may be a useful therapeutic strategy to overcome cisplatin resistance by preventing cyto-protective autophagy in ovarian cancer. Note: This abstract was not presented at the meeting. Citation Format: Jun He, Jing-Jie Yu, Bing-Hua Jiang. EGR1-MIR152 pathway overcomes acquired cisplatin resistance in ovarian cancer cells by inhibiting cyto-protective autophagy via ATG14. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4429. doi:10.1158/1538-7445.AM2015-4429