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Knockdown of cyclophilin A reverses paclitaxel resistance in human endometrial cancer cells via suppression of MAPK kinase pathways

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Abstract

Purpose

Paclitaxel resistance remains to be a major obstacle to the chemotherapy of endometrial cancer. Using proteomic-based approach, we used to identify cyclophilin A (CypA) as a potential therapeutic target for endometrial cancer. As a natural continuation, this study aimed to reveal the correlation between CypA and paclitaxel resistance and evaluate the possibility of CypA as a therapeutic target for reversal of resistance.

Methods

Two paclitaxel-resistant endometrial cancer cell sublines HEC-1-B/TAX and AN3CA/TAX were generated, and expressions of CypA, P-gp, MRP-2 and survivin were demonstrated by Western blotting. CypA was knocked down by RNA interference, and the subsequent effects on the alteration of paclitaxel resistance were examined by MTT, flow cytometry and migratory/invasive transwell assays. MAPK kinases activities were examined by Western blotting.

Results

CypA knockdown led to significant inhibition of cell proliferation, induction of apoptosis and suppression of migratory/invasive capacity in HEC-1-B/TAX and AN3CA/TAX cells when exposed to paclitaxel. CypA knockdown led to reductions in total and phosphorylated MAPK kinases, including Akt, ERK1/2, p38 MAPK and JNK, in HEC-1-B/TAX cells. Furthermore, pretreatment with MAPK kinase inhibitors exhibited a synergistic effect in combination with CypA knockdown.

Conclusions

These results demonstrated that CypA expression was up-regulated in paclitaxel-resistant cancer cells, and knockdown of CypA could reverse the paclitaxel resistance through, at least partly, suppression of MAPK kinase pathways, presenting a possibility of CypA serving as a therapeutic target to overcome paclitaxel resistance.

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Acknowledgments

This research was supported by Natural Science Foundation of China (Grant Numbers: 30901594 and 81170592) and Special Fund from National Excellent Doctoral Dissertation (Grant Number: 201079).

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Authors and Affiliations

  1. Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China

    Zhengyu Li & Jinhai Gou

  2. Department of Psychosomatic Medicine, People’s Hospital of Sichuan Province, Chengdu, People’s Republic of China

    Wenjiao Min

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  1. Zhengyu Li
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Correspondence to Zhengyu Li.

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Li, Z., Min, W. & Gou, J. Knockdown of cyclophilin A reverses paclitaxel resistance in human endometrial cancer cells via suppression of MAPK kinase pathways. Cancer Chemother Pharmacol 72, 1001–1011 (2013). https://doi.org/10.1007/s00280-013-2285-8

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  • DOI: https://doi.org/10.1007/s00280-013-2285-8

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