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CIP2A is associated with multidrug resistance in cervical adenocarcinoma by a P-glycoprotein pathway

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Tumor Biology

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.

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Acknowledgments

This research was supported by the National Natural Science Foundation of China (grant no. 81000733), Shandong Province Natural Science Foundation (grant nos. ZR2011HQ036 and ZR2012HM031), and the National Natural Science Foundation of China (grant nos. 81101259 and 81472552).

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    Authors and Affiliations

    1. Department of Pathology, School of Medicine, Shandong University, Jinan, People’s Republic of China

      Jing Hu, Zhiqiang Zhou, Chunyan Zhang & Xiao Wang

    2. 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

      Juan Liu, Xiaoli Zhang, Mei Qi, Weifang Zhang & Weiming Zhao

    3. Department of Radiation Oncology, Qi Lu hospital of Shandong University, Jinan, People’s Republic of China

      Meng Wang & Qingwei Wang

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    1. Juan Liu
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    Correspondence to Xiao Wang.

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    Juan Liu and Meng Wang contributed equally to this work.

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    Liu, J., Wang, M., Zhang, X. et al. CIP2A is associated with multidrug resistance in cervical adenocarcinoma by a P-glycoprotein pathway. Tumor Biol. 37, 2673–2682 (2016). https://doi.org/10.1007/s13277-015-4032-8

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    • DOI: https://doi.org/10.1007/s13277-015-4032-8

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