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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 promotes breast cancer apoptosis.(A) MCF7, ZR-75-1, MDA-MB-231 and SUM1315 cells treated with or without phenformin were double-stained with Annexin V and PI, and then analyzed by flow cytometry. (B) The percentages of Annexin V+/PI- cells(early apoptosis) were plotted. (C) Cell extracts were analyzed by western blotting to detect the expression of cleaved caspase 3 and GAPDH. (D) Expression ratio of cleaved caspase 3 to GAPDH. 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. Phenformin-treated cells were labeled as P and control cells were labeled as C.
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pone.0131207.g004: Phenformin promotes breast cancer apoptosis.(A) MCF7, ZR-75-1, MDA-MB-231 and SUM1315 cells treated with or without phenformin were double-stained with Annexin V and PI, and then analyzed by flow cytometry. (B) The percentages of Annexin V+/PI- cells(early apoptosis) were plotted. (C) Cell extracts were analyzed by western blotting to detect the expression of cleaved caspase 3 and GAPDH. (D) Expression ratio of cleaved caspase 3 to GAPDH. 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. Phenformin-treated cells were labeled as P and control cells were labeled as C.

Mentions: Breast cancer cells treated with phenformin were double-stained with Annexin V and PI, and the cellular apoptosis rates were determined by flow cytometry. In cells treated with phenformin, Annexin V+/PI- (early apoptosis) subpopulation significantly increased. Compared with control cells, the early apoptosis rates of phenformin-treated MCF7, ZR-75-1, MDA-MB-231 and SUM1315 cells increased to 7.56% (p = 0.043), 3.46% (p = 0.0145), 8.09% (p = 0.021) and 4.21% (p = 0.0425), respectively (Fig 4A and 4B). To further confirm the induction of apoptosis by phenformin, we detected the expression of cleaved caspase 3 by western blotting. Interestingly, cleaved caspase 3 levels significantly increased in ZR-75-1 and MDA-MB-231 breast cancer cells treated with phenformin, suggesting that the caspase 3 pathway may be involved in phenformin induced apoptosis (Fig 4C and 4D).


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 promotes breast cancer apoptosis.(A) MCF7, ZR-75-1, MDA-MB-231 and SUM1315 cells treated with or without phenformin were double-stained with Annexin V and PI, and then analyzed by flow cytometry. (B) The percentages of Annexin V+/PI- cells(early apoptosis) were plotted. (C) Cell extracts were analyzed by western blotting to detect the expression of cleaved caspase 3 and GAPDH. (D) Expression ratio of cleaved caspase 3 to GAPDH. 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. Phenformin-treated cells were labeled as P and control cells were labeled as C.
© Copyright Policy
Related In: Results  -  Collection

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pone.0131207.g004: Phenformin promotes breast cancer apoptosis.(A) MCF7, ZR-75-1, MDA-MB-231 and SUM1315 cells treated with or without phenformin were double-stained with Annexin V and PI, and then analyzed by flow cytometry. (B) The percentages of Annexin V+/PI- cells(early apoptosis) were plotted. (C) Cell extracts were analyzed by western blotting to detect the expression of cleaved caspase 3 and GAPDH. (D) Expression ratio of cleaved caspase 3 to GAPDH. 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. Phenformin-treated cells were labeled as P and control cells were labeled as C.
Mentions: Breast cancer cells treated with phenformin were double-stained with Annexin V and PI, and the cellular apoptosis rates were determined by flow cytometry. In cells treated with phenformin, Annexin V+/PI- (early apoptosis) subpopulation significantly increased. Compared with control cells, the early apoptosis rates of phenformin-treated MCF7, ZR-75-1, MDA-MB-231 and SUM1315 cells increased to 7.56% (p = 0.043), 3.46% (p = 0.0145), 8.09% (p = 0.021) and 4.21% (p = 0.0425), respectively (Fig 4A and 4B). To further confirm the induction of apoptosis by phenformin, we detected the expression of cleaved caspase 3 by western blotting. Interestingly, cleaved caspase 3 levels significantly increased in ZR-75-1 and MDA-MB-231 breast cancer cells treated with phenformin, suggesting that the caspase 3 pathway may be involved in phenformin induced apoptosis (Fig 4C and 4D).

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