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Downregulation of ATG14 by EGR1-MIR152 sensitizes ovarian cancer cells to cisplatin-induced apoptosis by inhibiting cyto-protective autophagy.
Autophagy. 2015; 11(2):373-84.A

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+Show Affiliations

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.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25650716

Citation

He, Jun, et al. "Downregulation of ATG14 By EGR1-MIR152 Sensitizes Ovarian Cancer Cells to Cisplatin-induced Apoptosis By Inhibiting Cyto-protective Autophagy." Autophagy, vol. 11, no. 2, 2015, pp. 373-84.
He J, Yu JJ, Xu Q, et al. Downregulation of ATG14 by EGR1-MIR152 sensitizes ovarian cancer cells to cisplatin-induced apoptosis by inhibiting cyto-protective autophagy. Autophagy. 2015;11(2):373-84.
He, J., Yu, J. J., Xu, Q., Wang, L., Zheng, J. Z., Liu, L. Z., & Jiang, B. H. (2015). Downregulation of ATG14 by EGR1-MIR152 sensitizes ovarian cancer cells to cisplatin-induced apoptosis by inhibiting cyto-protective autophagy. Autophagy, 11(2), 373-84. https://doi.org/10.1080/15548627.2015.1009781
He J, et al. Downregulation of ATG14 By EGR1-MIR152 Sensitizes Ovarian Cancer Cells to Cisplatin-induced Apoptosis By Inhibiting Cyto-protective Autophagy. Autophagy. 2015;11(2):373-84. PubMed PMID: 25650716.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Downregulation of ATG14 by EGR1-MIR152 sensitizes ovarian cancer cells to cisplatin-induced apoptosis by inhibiting cyto-protective autophagy. AU - He,Jun, AU - Yu,Jing-Jie, AU - Xu,Qing, AU - Wang,Lin, AU - Zheng,Jenny Z, AU - Liu,Ling-Zhi, AU - Jiang,Bing-Hua, PY - 2015/2/5/entrez PY - 2015/2/5/pubmed PY - 2016/1/27/medline KW - ANXA5, annexin A5 KW - ATG14 KW - ATG14, autophagy-related 14 KW - CSF1, colony stimulating factor 1 (macrophage) KW - EGR1 KW - EGR1, early growth response 1 KW - ERCC1 KW - ERCC1, excision repair cross-complementation group 1 KW - FOXO, forkhead box O KW - GFP, green fluorescent protein KW - MAPILC3/LC3, microtubule-associated protein 1 light chain 3 KW - MIR152 KW - MTOR, mechanistic target of rapamycin KW - PI, propidium iodide KW - RPS6KB1, ribosomal protein S6 kinase, 70kDa, polypeptide 1 KW - SQSTM1, sequestosome 1 KW - autophagy KW - cisplatin-resistance KW - ovarian cancer SP - 373 EP - 84 JF - Autophagy JO - Autophagy VL - 11 IS - 2 N2 - 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. SN - 1554-8635 UR - https://www.unboundmedicine.com/medline/citation/25650716/Downregulation_of_ATG14_by_EGR1_MIR152_sensitizes_ovarian_cancer_cells_to_cisplatin_induced_apoptosis_by_inhibiting_cyto_protective_autophagy_ L2 - http://www.tandfonline.com/doi/full/10.1080/15548627.2015.1009781 DB - PRIME DP - Unbound Medicine ER -