title: CIP2A is associated with multidrug resistance in cervical adenocarcinoma by a P-glycoprotein pathway.
abstract: Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently identified oncoprotein. Here, we investigated its role in the formation of multidrug resistance (MDR) of cervical adenocarcinoma in vitro and in vivo. MTT assay showed that knockdown of CIP2A expression increased the drug sensitivity of HeLa and Dox-resistant HeLa cells (HeLa-Dox) to doxorubicin, cisplatin, and paclitaxel significantly, while overexpression of CIP2A decreased the sensitivity of HeLa cells to chemo-drugs dramatically. When treated with different chemotherapeutics, CIP2A and P-glycoprotein (P-gp) protein levels were increased in HeLa cells simultaneously. In accordance with it, knockdown or overexpression of CIP2A expression inhibited or increased the P-gp expression in the transcription level separately. The effects of CIP2A on P-gp expression was achieved partly through its regulation on the transcription factor E2F1. Moreover, the interference of CIP2A could decrease the P-gp protein activity elucidated by Rhodamine 123 (Rh123) efflux assay in HeLa and HeLa/Dox cells. In the in vivo level, confocal microscopy data demonstrated the strong co-localization of CIP2A and P-gp protein in HeLa cells, and CIP2A protein expression was significantly associated with that of P-gp in cervical adenocarcinoma tissues. Thus, CIP2A is involved in regulating multidrug resistance of cervical adenocarcinoma upon chemotherapy by enhancing P-gp expression through E2F1. CIP2A may be an attractive target in anticancer strategies to improve the effect of chemotherapy in cervical adenocarcinoma.
authors.affiliation: Department of Microbiology and Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, People's Republic of China.
authors.forename: Juan
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Radiation Oncology, Qi Lu hospital of Shandong University, Jinan, People's Republic of China.
authors.forename: Meng
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Microbiology and Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, People's Republic of China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Radiation Oncology, Qi Lu hospital of Shandong University, Jinan, People's Republic of China.
authors.forename: Qingwei
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Microbiology and Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, People's Republic of China.
authors.forename: Mei
authors.initials: M
authors.lastname: Qi
authors.affiliation: Department of Pathology, School of Medicine, Shandong University, Jinan, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Pathology, School of Medicine, Shandong University, Jinan, People's Republic of China.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of Pathology, School of Medicine, Shandong University, Jinan, People's Republic of China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Microbiology and Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, People's Republic of China.
authors.forename: Weifang
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Microbiology and Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, People's Republic of China.
authors.forename: Weiming
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Pathology, School of Medicine, Shandong University, Jinan, People's Republic of China. wangxiao08@sdu.edu.cn.
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics*; D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001324:Autoantigens / Q000235:genetics*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use; D004317:Doxorubicin / Q000627:therapeutic use; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D017239:Paclitaxel / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000235:genetics*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D001324:Autoantigens; C500266:CIP2A protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D004317:Doxorubicin; D017239:Paclitaxel; D002945:Cisplatin
keywords: Cancerous inhibitor of protein phosphatase 2A; Cervical cancer; Chemotherapy; Multidrug resistance; P-glycoprotein