title: Metformin promotes autophagy and apoptosis in esophageal squamous cell carcinoma by downregulating Stat3 signaling.
abstract: 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.
authors.affiliation: 1] Department of Integrative Oncology, Affiliated Cancer Hospital of Shantou University Medical College, Shantou, China [2] Cancer Research Center, Shantou University Medical College, Shantou, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Cancer Research Center, Shantou University Medical College, Shantou, China.
authors.forename: C
authors.initials: C
authors.lastname: Ke
authors.affiliation: 1] Department of Integrative Oncology, Affiliated Cancer Hospital of Shantou University Medical College, Shantou, China [2] Cancer Research Center, Shantou University Medical College, Shantou, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Tang
authors.affiliation: Cancer Research Center, Shantou University Medical College, Shantou, China.
authors.forename: H
authors.initials: H
authors.lastname: Dong
authors.affiliation: Cancer Research Center, Shantou University Medical College, Shantou, China.
authors.forename: X
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Cancer Research Center, Shantou University Medical College, Shantou, China.
authors.forename: W
authors.initials: W
authors.lastname: Lin
authors.affiliation: 1] Department of Integrative Oncology, Affiliated Cancer Hospital of Shantou University Medical College, Shantou, China [2] Cancer Research Center, Shantou University Medical College, Shantou, China.
authors.forename: J
authors.initials: J
authors.lastname: Ke
authors.affiliation: Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou, China.
authors.forename: J
authors.initials: J
authors.lastname: Huang
authors.affiliation: 1] Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center, Houston, TX, USA [2] Department of Emergency Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: S-C J
authors.initials: SC
authors.lastname: Yeung
authors.affiliation: 1] Department of Integrative Oncology, Affiliated Cancer Hospital of Shantou University Medical College, Shantou, China [2] Cancer Research Center, Shantou University Medical College, Shantou, China [3] Tumor Tissue Bank, Affiliated Cancer Hospital of Shantou University Medical College, Shantou, China.
authors.forename: H
authors.initials: H
authors.lastname: Zhang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D008687:Metformin; D055372:AMP-Activated Protein Kinases