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BMC Cancer
Published in: BMC Cancer 1/2017

Open Access 01-12-2017 | Research article

Inhibition of the IGF signaling pathway reverses cisplatin resistance in ovarian cancer cells

Authors: Juan Du, Hui-rong Shi, Fang Ren, Jing-lu Wang, Qing-hua Wu, Xia Li, Rui-tao Zhang

Published in: BMC Cancer | Issue 1/2017

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Abstract

Background

This study was aimed at investigating whether metformin can reverse the resistance of ovarian cancer cells to cisplatin and exploring the underlying mechanism.

Methods

Ovarian cancer cell proliferation in vitro was evaluated using a CCK-8 assay. The resistance index of platinum-resistant ovarian cancer cells was determined and cell cycle and apoptosis rate determined by annexin V/propidium iodide double-staining in CP70 cells. Western blotting was used to determine IGF1, IGF1R, AKT, p-IGF1, p-IGF1R, p-AKT, and MRP2 levels in cells treated with different concentrations of metformin and LY29400, an inhibitor of the insulin-like growth factor pathway. Changes in gene expression levels of MRP2, IGF1, IGF1R, and AKT were determined by fluorescence real-time quantitative PCR assay of CP70 cells treated with metformin. Tumors of human ovarian cancer cell lines CP70 and A2780 were established by subcutaneous transplantation of cells in nude mice and the effect of metformin on MRP2 expression and tumor inhibition assessed.

Results

The IC50 value of cisplatin in CP70 cells decreased significantly as metformin concentration increased (P < 0.05). The cell cycle distribution in CP70 cells changed with metformin treatment; the percentage of cells in the G0/G1 phase, as well as the natural apoptosis rate was significantly increased with metformin treatment (P < 0.05). IGF1, IGF1R, AKT p-IGF1, p-IGF1R, and p-Akt protein expression was enhanced dose-dependently with metformin, and was also significantly changed by treatment of CP70 cells with 0 mM metformin +10 mM LY294002. Moreover, changes in the expression of MRP2, IGF1, IGF1R, and AKT was metformin-concentration dependent, and was significantly different from that in the untreated control group (P < 0.05). In nude mice, the tumor volumes of the cisplatin-treated groups were significantly less than in the control group, and was further suppressed by co-treatment with cisplatin and metformin (P < 0.05), indicating that these 2 drugs had a synergistic effect on tumor inhibition.

Conclusion

Metformin can improve the sensitivity of ovarian cancer CP70 cells to cisplatin in a concentration-dependent manner by activating the AKT signaling pathway, inhibiting the IGF1R signaling pathway, and reducing MRP2 expression.
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Metadata
Title
Inhibition of the IGF signaling pathway reverses cisplatin resistance in ovarian cancer cells
Authors
Juan Du
Hui-rong Shi
Fang Ren
Jing-lu Wang
Qing-hua Wu
Xia Li
Rui-tao Zhang
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2017
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-017-3840-1

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