title: Knockdown of MACC1 expression increases cisplatin sensitivity in cisplatin-resistant epithelial ovarian cancer cells.
abstract: Abnormal expression of metastasis-associated in colon cancer 1 (MACC1) was found to be closely associated with several types of malignant tumors. The present study aimed to verify the relationship between MACC1 and cisplatin resistance in ovarian cancer cells and the possible mechanisms, which was implemented by inhibition of the expression of MACC1 in cisplatin-resistant human ovarian cancer cell lines A2780/DDP and COC1/DDP. MACC1 shRNA eukaryotic plasmids and negative control plasmids were transfected into A2780/DDP and COC1/DDP cells, respectively, while A2780/DDP and COC1/DDP cells were used as blank controls. Western blotting and sqRT-PCR were used to detect the expression of MACC1 in the different cell groups. Different concentrations of cispaltin (0, 10, 20, 30, 40, 50 and 60 µmol/l) were used to treat the cell groups, respectively, and then the chemosensitivity of cisplatin and cell apoptosis were examined by MTT and flow cytometry, respectively. The activity of caspase-3 was determined by spectrophotometry. Expression levels of p-ERK1/2, permeability glycoprotein (P-gp), B-cell lymphoma 2 (Bcl-2), Bcl-XL, Bax and Bad protein were detected in the different ovarian cancer cells by western blotting. After MACC1 knockdown, the chemosensitivity of cisplatin in the ovarian cancer cells was enhanced, and the cell growth inhibition and apoptosis rates were increased. The expression levels of Bax and Bad were upregulated, the activity of caspase-3 was increased, while the expression levels of p-ERK1/2, P-gp, Bcl-2 and Bcl-XL were downregulated as a result of MACC1 inhibition. These results indicate that inhibition of MACC1 improves the chemosensitivity of cisplatin in epithelial ovarian cancer cells, through the regulation of the ERK1/2 signaling pathway on P-gp and its downstream apoptosis proteins.
authors.affiliation: Department of Gynaecology, First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.
authors.forename: Ruitao
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Gynaecology, First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.
authors.forename: Huirong
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Gynaecology, First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.
authors.forename: Fang
authors.initials: F
authors.lastname: Ren
authors.affiliation: Department of Gynaecology, First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Gynaecology, First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.
authors.forename: Minghui
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Gynaecology, First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Feng
authors.affiliation: Department of Gynaecology, First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Jia
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077216:Carcinoma, Ovarian Epithelial; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques / Q000379:methods*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; C544162:MACC1 protein, human; D034741:RNA, Small Interfering; D015534:Trans-Activators; D014157:Transcription Factors; C505407:CASP3 protein, human; D053148:Caspase 3; D002945:Cisplatin