Inhibition of the IGF signaling pathway reverses cisplatin resistance in ovarian cancer cells
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-r...
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| Format: | Article |
| Language: | English |
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BMC
2017-12-01
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| Series: | BMC Cancer |
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| Online Access: | http://link.springer.com/article/10.1186/s12885-017-3840-1 |
| _version_ | 1819086788290936832 |
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| author | Juan Du Hui-rong Shi Fang Ren Jing-lu Wang Qing-hua Wu Xia Li Rui-tao Zhang |
| author_facet | Juan Du Hui-rong Shi Fang Ren Jing-lu Wang Qing-hua Wu Xia Li Rui-tao Zhang |
| author_sort | Juan Du |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T21:25:49Z |
| format | Article |
| id | doaj.art-86aa1f2a60824532b58c4392b659f09c |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-21T21:25:49Z |
| publishDate | 2017-12-01 |
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| series | BMC Cancer |
| spelling | doaj.art-86aa1f2a60824532b58c4392b659f09c2022-12-21T18:49:46ZengBMCBMC Cancer1471-24072017-12-0117111110.1186/s12885-017-3840-1Inhibition of the IGF signaling pathway reverses cisplatin resistance in ovarian cancer cellsJuan Du0Hui-rong Shi1Fang Ren2Jing-lu Wang3Qing-hua Wu4Xia Li5Rui-tao Zhang6Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou UniversityAbstract 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.http://link.springer.com/article/10.1186/s12885-017-3840-1CisplatinDNA repairDrug resistanceHematoxylin and eosin stainingImmunohistochemistryInsulin-like growth factor signaling pathway |
| spellingShingle | Juan Du Hui-rong Shi Fang Ren Jing-lu Wang Qing-hua Wu Xia Li Rui-tao Zhang Inhibition of the IGF signaling pathway reverses cisplatin resistance in ovarian cancer cells BMC Cancer Cisplatin DNA repair Drug resistance Hematoxylin and eosin staining Immunohistochemistry Insulin-like growth factor signaling pathway |
| title | Inhibition of the IGF signaling pathway reverses cisplatin resistance in ovarian cancer cells |
| title_full | Inhibition of the IGF signaling pathway reverses cisplatin resistance in ovarian cancer cells |
| title_fullStr | Inhibition of the IGF signaling pathway reverses cisplatin resistance in ovarian cancer cells |
| title_full_unstemmed | Inhibition of the IGF signaling pathway reverses cisplatin resistance in ovarian cancer cells |
| title_short | Inhibition of the IGF signaling pathway reverses cisplatin resistance in ovarian cancer cells |
| title_sort | inhibition of the igf signaling pathway reverses cisplatin resistance in ovarian cancer cells |
| topic | Cisplatin DNA repair Drug resistance Hematoxylin and eosin staining Immunohistochemistry Insulin-like growth factor signaling pathway |
| url | http://link.springer.com/article/10.1186/s12885-017-3840-1 |
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