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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

Activation of AMPK/mTOR/p70s6k signaling by phenformin.(A) MCF7, ZR-75-1, MDA-MB-231 and SUM1315 cells were treated with or without phenformin for 24 hours. Cell extracts were analyzed by western blotting to detect the expression of p-AMPK, AMPK, p-mTOR, mTOR, p-p70s6k, p70s6k and GAPDH. (B) Expression ratios analysis of p-AMPK to AMPK, (C) p-mTOR to mTOR, (D) p-p70s6k to p70s6k. The data are presented as 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.g005: Activation of AMPK/mTOR/p70s6k signaling by phenformin.(A) MCF7, ZR-75-1, MDA-MB-231 and SUM1315 cells were treated with or without phenformin for 24 hours. Cell extracts were analyzed by western blotting to detect the expression of p-AMPK, AMPK, p-mTOR, mTOR, p-p70s6k, p70s6k and GAPDH. (B) Expression ratios analysis of p-AMPK to AMPK, (C) p-mTOR to mTOR, (D) p-p70s6k to p70s6k. The data are presented as 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: Western blotting was performed to determine whether AMPK, mTOR and p70s6k were involved in phenformin-induced apoptosis. Notably, Thr172 phosphorylation within the alpha subunit of AMPK significantly increased in the phenformin group compared with the control group after a 24-hour treatment. Moreover, downstream of AMPK, phosphorylation at Ser2448 of mTOR and at Thr389 of p70s6k decreased in response to phenformin compared with control. Meanwhile, there were no significant differences in total AMPK, mTOR or p70s6k expression between the control and phenformin-treated groups (Fig 5).


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)

Activation of AMPK/mTOR/p70s6k signaling by phenformin.(A) MCF7, ZR-75-1, MDA-MB-231 and SUM1315 cells were treated with or without phenformin for 24 hours. Cell extracts were analyzed by western blotting to detect the expression of p-AMPK, AMPK, p-mTOR, mTOR, p-p70s6k, p70s6k and GAPDH. (B) Expression ratios analysis of p-AMPK to AMPK, (C) p-mTOR to mTOR, (D) p-p70s6k to p70s6k. The data are presented as 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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Show All Figures
getmorefigures.php?uid=PMC4482683&req=5

pone.0131207.g005: Activation of AMPK/mTOR/p70s6k signaling by phenformin.(A) MCF7, ZR-75-1, MDA-MB-231 and SUM1315 cells were treated with or without phenformin for 24 hours. Cell extracts were analyzed by western blotting to detect the expression of p-AMPK, AMPK, p-mTOR, mTOR, p-p70s6k, p70s6k and GAPDH. (B) Expression ratios analysis of p-AMPK to AMPK, (C) p-mTOR to mTOR, (D) p-p70s6k to p70s6k. The data are presented as 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: Western blotting was performed to determine whether AMPK, mTOR and p70s6k were involved in phenformin-induced apoptosis. Notably, Thr172 phosphorylation within the alpha subunit of AMPK significantly increased in the phenformin group compared with the control group after a 24-hour treatment. Moreover, downstream of AMPK, phosphorylation at Ser2448 of mTOR and at Thr389 of p70s6k decreased in response to phenformin compared with control. Meanwhile, there were no significant differences in total AMPK, mTOR or p70s6k expression between the control and phenformin-treated groups (Fig 5).

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