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Phenformin Induces Cell Cycle Change, Apoptosis, and Mesenchymal-Epithelial Transition and Regulates the AMPK/mTOR/p70s6k and MAPK/ERK Pathways in Breast Cancer Cells.

Liu Z, Ren L, Liu C, Xia T, Zha X, Wang S - PLoS ONE (2015)

Bottom Line: Emerging evidence has demonstrated the potent anti-tumor effect of biguanides, among which phenformin was reported to potentially be a more active anti-cancer agent than metformin.Furthermore, our results suggest that phenformin inhibits breast cancer cell metastasis after intracardiac injection into nude mice.Taken together, our study further confirms the potential benefit of phenformin in breast cancer treatment and provides novel mechanistic insight into its anti-cancer activity in breast cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Breast Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

ABSTRACT
Breast cancer remains a world-wide challenge, and additional anti-cancer therapies are still urgently needed. Emerging evidence has demonstrated the potent anti-tumor effect of biguanides, among which phenformin was reported to potentially be a more active anti-cancer agent than metformin. However, little attention has been given to the role of phenformin in breast cancer. In this study, we reveal the role of phenformin in cell death of the MCF7, ZR-75-1, MDA-MB-231 and SUM1315 breast cancer cell lines. The respective IC50 values of phenformin in MCF7, ZR-75-1, MDA-MB-231 and SUM1315 cells were 1.184±0.045 mM, 0.665±0.007 mM, 2.347±0.010 mM and 1.885±0.015 mM (mean± standard error). Phenformin induced cell cycle change and apoptosis in breast cancer cells via the AMPK/mTOR/p70s6k and MAPK/ERK pathways. Interestingly, phenformin induced MET (mesenchymal-epithelial transition) and decreased the migration rate in breast cancer cell lines. Furthermore, our results suggest that phenformin inhibits breast cancer cell metastasis after intracardiac injection into nude mice. Taken together, our study further confirms the potential benefit of phenformin in breast cancer treatment and provides novel mechanistic insight into its anti-cancer activity in breast cancer.

No MeSH data available.


Related in: MedlinePlus

Phenformin inhibits MDA-MB-231 cells migration.(A) After incubation with phenformin for 24 hours, MDA-MB-231 cells (25,000 cells per chamber) were seeded in the upper chamber in serum free medium. The lower chamber contained medium with 10% FBS. After incubation for 16 hours, the cells were removed from the upper surface of the chamber membrane, and the cells on the lower surface of the chamber were stained with crystal violet and counted using a microscope(100X). (B) The number of cells/five fields was plotted. The data are presented as the mean±SEM of three replicates per group. Asterisks indicate significant differences at p<0.05 by Student’s t test.
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pone.0131207.g007: Phenformin inhibits MDA-MB-231 cells migration.(A) After incubation with phenformin for 24 hours, MDA-MB-231 cells (25,000 cells per chamber) were seeded in the upper chamber in serum free medium. The lower chamber contained medium with 10% FBS. After incubation for 16 hours, the cells were removed from the upper surface of the chamber membrane, and the cells on the lower surface of the chamber were stained with crystal violet and counted using a microscope(100X). (B) The number of cells/five fields was plotted. The data are presented as the mean±SEM of three replicates per group. Asterisks indicate significant differences at p<0.05 by Student’s t test.

Mentions: Phenformin treatment significantly increased the expression of the epithelial marker E-cadherin in MDA-MB-231 cells. Moderate changes in E-cadherin expression were observed in MCF-7, ZR-75-1 and SUM1315 cells. In contrast, the mesenchymal marker vimentin was significantly downregulated in all the cell lines after treatment with phenformin (Fig 6). Our findings indicated that phenformin might induce MET and prevent breast cancer metastasis. As the MDA-MB-231 cell line is the least sensitive of the four cell lines to phenformin-induced growth inhibition and the most aggressive among the four breast cancer cell lines, we utilized MDA-MB-231 cells to further evaluate the role of phenformin in breast cancer metastasis. Interestingly, the migration rate of phenformin-treated MDA-MB-231 cells was significantly decreased compared with control cells (Fig 7). Furthermore, four weeks after intracardiac injection of MDA-MB-231 cells, the total flux of the nude mice in the phenformin group was significantly lower than that in the control group (p = 0.0065) (Fig 8), which indicated that phenformin might inhibit breast cancer metastasis.


Phenformin Induces Cell Cycle Change, Apoptosis, and Mesenchymal-Epithelial Transition and Regulates the AMPK/mTOR/p70s6k and MAPK/ERK Pathways in Breast Cancer Cells.

Liu Z, Ren L, Liu C, Xia T, Zha X, Wang S - PLoS ONE (2015)

Phenformin inhibits MDA-MB-231 cells migration.(A) After incubation with phenformin for 24 hours, MDA-MB-231 cells (25,000 cells per chamber) were seeded in the upper chamber in serum free medium. The lower chamber contained medium with 10% FBS. After incubation for 16 hours, the cells were removed from the upper surface of the chamber membrane, and the cells on the lower surface of the chamber were stained with crystal violet and counted using a microscope(100X). (B) The number of cells/five fields was plotted. The data are presented as the mean±SEM of three replicates per group. Asterisks indicate significant differences at p<0.05 by Student’s t test.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4482683&req=5

pone.0131207.g007: Phenformin inhibits MDA-MB-231 cells migration.(A) After incubation with phenformin for 24 hours, MDA-MB-231 cells (25,000 cells per chamber) were seeded in the upper chamber in serum free medium. The lower chamber contained medium with 10% FBS. After incubation for 16 hours, the cells were removed from the upper surface of the chamber membrane, and the cells on the lower surface of the chamber were stained with crystal violet and counted using a microscope(100X). (B) The number of cells/five fields was plotted. The data are presented as the mean±SEM of three replicates per group. Asterisks indicate significant differences at p<0.05 by Student’s t test.
Mentions: Phenformin treatment significantly increased the expression of the epithelial marker E-cadherin in MDA-MB-231 cells. Moderate changes in E-cadherin expression were observed in MCF-7, ZR-75-1 and SUM1315 cells. In contrast, the mesenchymal marker vimentin was significantly downregulated in all the cell lines after treatment with phenformin (Fig 6). Our findings indicated that phenformin might induce MET and prevent breast cancer metastasis. As the MDA-MB-231 cell line is the least sensitive of the four cell lines to phenformin-induced growth inhibition and the most aggressive among the four breast cancer cell lines, we utilized MDA-MB-231 cells to further evaluate the role of phenformin in breast cancer metastasis. Interestingly, the migration rate of phenformin-treated MDA-MB-231 cells was significantly decreased compared with control cells (Fig 7). Furthermore, four weeks after intracardiac injection of MDA-MB-231 cells, the total flux of the nude mice in the phenformin group was significantly lower than that in the control group (p = 0.0065) (Fig 8), which indicated that phenformin might inhibit breast cancer metastasis.

Bottom Line: Emerging evidence has demonstrated the potent anti-tumor effect of biguanides, among which phenformin was reported to potentially be a more active anti-cancer agent than metformin.Furthermore, our results suggest that phenformin inhibits breast cancer cell metastasis after intracardiac injection into nude mice.Taken together, our study further confirms the potential benefit of phenformin in breast cancer treatment and provides novel mechanistic insight into its anti-cancer activity in breast cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Breast Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

ABSTRACT
Breast cancer remains a world-wide challenge, and additional anti-cancer therapies are still urgently needed. Emerging evidence has demonstrated the potent anti-tumor effect of biguanides, among which phenformin was reported to potentially be a more active anti-cancer agent than metformin. However, little attention has been given to the role of phenformin in breast cancer. In this study, we reveal the role of phenformin in cell death of the MCF7, ZR-75-1, MDA-MB-231 and SUM1315 breast cancer cell lines. The respective IC50 values of phenformin in MCF7, ZR-75-1, MDA-MB-231 and SUM1315 cells were 1.184±0.045 mM, 0.665±0.007 mM, 2.347±0.010 mM and 1.885±0.015 mM (mean± standard error). Phenformin induced cell cycle change and apoptosis in breast cancer cells via the AMPK/mTOR/p70s6k and MAPK/ERK pathways. Interestingly, phenformin induced MET (mesenchymal-epithelial transition) and decreased the migration rate in breast cancer cell lines. Furthermore, our results suggest that phenformin inhibits breast cancer cell metastasis after intracardiac injection into nude mice. Taken together, our study further confirms the potential benefit of phenformin in breast cancer treatment and provides novel mechanistic insight into its anti-cancer activity in breast cancer.

No MeSH data available.


Related in: MedlinePlus