TY - JOUR
T1 - Metformin promotes autophagy and apoptosis in esophageal squamous cell carcinoma by downregulating Stat3 signaling
AU - Feng, Y.
AU - Ke, C.
AU - Tang, Q.
AU - Dong, H.
AU - Zheng, X.
AU - Lin, W.
AU - Ke, J.
AU - Huang, J.
AU - Yeung, S. C.J.
AU - Zhang, H.
N1 - Funding Information:
Acknowledgements. This work was supported by National Natural Science Foundation of China (81071736 and 30973508) and the Research Fund for the Doctoral Program of Higher Education of China (RFDP, 20104402110005). The immortalized NE3 cells was a kind gift from Dr. SW Tsao at Hong Kong University. We thank Dr. Xiao-kun Zhang (Burnham Institute, USA) and Dr. Jinzhang Zeng (Xiamen University, China) for kindly providing plasmids (pEGFP-LC3 and Bcl-2). We thank Lin Zheng, Jinfeng Gan and Hongcai Chen for their technical assistance. We thank Dr. Stanley Lin for proofreading.
PY - 2014/2
Y1 - 2014/2
N2 - The antidiabetic drug metformin exerts chemopreventive and antineoplastic effects in many types of malignancies. However, the mechanisms responsible for metformin actions appear diverse and may differ in different types of cancer. Understanding the molecular and cellular mechanisms specific for different cancers is important to optimize strategy for metformin treatment in different cancer types. Here, we investigate the in vitro and in vivo effects of metformin on esophageal squamous cell carcinoma (ESCC) cells. Metformin selectively inhibited cell growth in ESCC tumor cells but not immortalized noncancerous esophageal epithelial cells. In addition to apoptosis, metformin triggered autophagy. Pharmacological or genetic inhibition of autophagy sensitized ESCC cells to metformin-induced apoptotic cell death. Mechanistically, signal transducer and activator of transcription 3 (Stat3) and its downstream target Bcl-2 was inactivated by metformin treatment. Accordingly, small interfering RNA (siRNA)-mediated Stat3 knockdown enhanced metformin-induced autophagy and apoptosis, and concomitantly enhanced the inhibitory effect of metformin on cell viability. Similarly, the Bcl-2 proto-oncogene, an inhibitor of both apoptosis and autophagy, was repressed by metformin. Ectopic expression of Bcl-2 protected cells from metformin-mediated autophagy and apoptosis. In vivo, metformin downregulated Stat3 activity and Bcl-2 expression, induced apoptosis and autophagy, and inhibited tumor growth. Together, inactivation of Stat3-Bcl-2 pathway contributes to metformin-induced growth inhibition of ESCC by facilitating crosstalk between apoptosis and autophagy.
AB - The antidiabetic drug metformin exerts chemopreventive and antineoplastic effects in many types of malignancies. However, the mechanisms responsible for metformin actions appear diverse and may differ in different types of cancer. Understanding the molecular and cellular mechanisms specific for different cancers is important to optimize strategy for metformin treatment in different cancer types. Here, we investigate the in vitro and in vivo effects of metformin on esophageal squamous cell carcinoma (ESCC) cells. Metformin selectively inhibited cell growth in ESCC tumor cells but not immortalized noncancerous esophageal epithelial cells. In addition to apoptosis, metformin triggered autophagy. Pharmacological or genetic inhibition of autophagy sensitized ESCC cells to metformin-induced apoptotic cell death. Mechanistically, signal transducer and activator of transcription 3 (Stat3) and its downstream target Bcl-2 was inactivated by metformin treatment. Accordingly, small interfering RNA (siRNA)-mediated Stat3 knockdown enhanced metformin-induced autophagy and apoptosis, and concomitantly enhanced the inhibitory effect of metformin on cell viability. Similarly, the Bcl-2 proto-oncogene, an inhibitor of both apoptosis and autophagy, was repressed by metformin. Ectopic expression of Bcl-2 protected cells from metformin-mediated autophagy and apoptosis. In vivo, metformin downregulated Stat3 activity and Bcl-2 expression, induced apoptosis and autophagy, and inhibited tumor growth. Together, inactivation of Stat3-Bcl-2 pathway contributes to metformin-induced growth inhibition of ESCC by facilitating crosstalk between apoptosis and autophagy.
KW - Bcl-2
KW - Stat3
KW - apoptosis
KW - autophagy
KW - esophageal squamous cell carcinoma
KW - metformin
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U2 - 10.1038/cddis.2014.59
DO - 10.1038/cddis.2014.59
M3 - Article
C2 - 24577086
AN - SCOPUS:84896776849
SN - 2041-4889
VL - 5
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 2
M1 - e1088
ER -