title: MiR-489 modulates cisplatin resistance in human ovarian cancer cells by targeting Akt3.
abstract: MicroRNAs are a conserved class of small noncoding RNA molecules that harbour the capacity to regulate protein-coding gene expression at the post-transcriptional level. In the current study, we show that miR-489 is downregulated in cisplatin (CDDP)-resistant ovarian cancer cells, SKOV3/CDDP and OVCAR3/CDDP cells. MiR-489 overexpression results in an inhibition of SKOV3 and OVCAR3 cell survival and cell growth after CDDP treatment and an induction of cell apoptosis. Inhibition of miR-489 yields the opposite results. In addition, miR-489 overexpression increases the sensitivity of SKOV3/CDDP and OVCAR3/CDDP cells to CDDP and inhibits their colony number. Akt3 is validated as a direct target of miR-489 in SKOV3, OVCAR3, SKOV3/CDDP and OVCAR3/CDDP cells. In addition, miR-489 suppresses Akt3 protein expression by binding sites on its 3'UTR. Knockdown of Akt3 results in a similar effect as that because of miR-489 overexpression; importantly, Akt3 silencing rescues the functions induced by miR-489. Furthermore, we also use the Akt3 inhibitor, MK-2206 2HCl, to determine the role of Akt3 in CDDP resistance. Our study showed that MK-2206 2HCl increased the sensitivity of SKOV3/CDDP and OVCAR3/CDDP cells to CDDP. Taken together, our results indicate that miR-489 inhibited CDDP resistance and cell growth, and promotes apoptosis by suppressing Akt3 expression. Furthermore, the identification of a novel miR-489-based pathway in CDDP-resistant ovarian cancer will facilitate the development of therapeutic strategies.
authors.affiliation: aKey Laboratory of Cancer Prevention and Therapy, Department of Gynecological Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer bDepartment of Clinical Laboratory, The Affiliated Hospital of the Logistics University of Chinese People's Armed Police Forces, Tianjin cDepartment of Gynecology, Yongchuan Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Huijuan
authors.initials: H
authors.lastname: Wu
authors.forename: Zhenghua
authors.initials: Z
authors.lastname: Xiao
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Ke
authors.initials: K
authors.lastname: Wang
authors.forename: Wenxin
authors.initials: W
authors.lastname: Liu
authors.forename: Quan
authors.initials: Q
authors.lastname: Hao
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D006575:Heterocyclic Compounds, 3-Ring; C552418:MIRN489 microRNA, human; C548887:MK 2206; D035683:MicroRNAs; C491754:AKT3 protein, human; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin