title: Downregulation of ATG14 by EGR1-MIR152 sensitizes ovarian cancer cells to cisplatin-induced apoptosis by inhibiting cyto-protective autophagy.
abstract: Cisplatin is commonly used in ovarian cancer treatment by inducing apoptosis in cancer cells as a result of lethal DNA damage. However, the intrinsic and acquired resistance to cisplatin in cancer cells remains a big challenge for improving overall survival. The cyto-protective functions of autophagy in cancer cells have been suggested as a potential mechanism for chemoresistance. 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 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.
authors: a State Key Lab of Reproductive Medicine and Department of Pathology ; Cancer Center ; Collaborative Innovation Center for Cancer Personalized Medicine; Nanjing Medical University ; Nanjing , China.
authors: Jun
authors: J
authors: He
authors: Jing-Jie
authors: JJ
authors: Yu
authors: Qing
authors: Q
authors: Xu
authors: Lin
authors: L
authors: Wang
authors: Jenny Z
authors: JZ
authors: Zheng
authors: Ling-Zhi
authors: LZ
authors: Liu
authors: Bing-Hua
authors: BH
authors: Jiang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D005260:Female; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C550856:MIRN152 microRNA, human; D035683:MicroRNAs; D002945:Cisplatin
keywords: ANXA5, annexin A5; ATG14; ATG14, autophagy-related 14; CSF1, colony stimulating factor 1 (macrophage); EGR1; EGR1, early growth response 1; ERCC1; ERCC1, excision repair cross-complementation group 1; FOXO, forkhead box O; GFP, green fluorescent protein; MAPILC3/LC3, microtubule-associated protein 1 light chain 3; MIR152; MTOR, mechanistic target of rapamycin; PI, propidium iodide; RPS6KB1, ribosomal protein S6 kinase, 70kDa, polypeptide 1; SQSTM1, sequestosome 1; autophagy; cisplatin-resistance; ovarian cancer
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