title: Metformin sensitizes chemotherapy by targeting cancer stem cells and the mTOR pathway in esophageal cancer.
abstract: Our clinical study indicates esophageal adenocarcinoma patients on metformin had a better treatment response than those without metformin. However, the effects of metformin and the mechanisms of its action in esophageal cancer (EC) are unclear. EC cell lines were used to assess the effects of metformin alone or in combination with 5-fluorouracil on survival and apoptosis. RPPA proteomic array and immunoblots were used to identify signaling affected by metformin. Standard descriptive statistical methods were used. Reduction in cell survival and induction of apoptosis by metformin were observed in several EC cell lines. The use of metformin in combination with 5-FU significantly sensitized EC cells to the cytotoxic effect of 5-FU. RPPA array demonstrated that metformin decreased various oncogenes including PI3K/mTORsignaling and survival/cancer stem cell-related genes in cells treated with metformin compared with its control. Immunoblots and transcriptional analyses further confirm that metformin downregulated these CSC-related genes and the components of the mTOR pathway in a dose‑dependent manner. Sorted ALDH-1+ cell tumor sphere forming capacity was preferentially reduced by metformin. Finally, metformin reduced tumor growth in vivo and when combined with FU, there was synergistic reduction in tumor growth. Metformin inhibits EC cell growth and sensitizes EC cells to 5-FU cytotoxic effects by targeting CSCs and the components of mTOR. The present study supports our previous clinical observations that the use of metformin is beneficial to EC patients. Metformin can complement other therapeutic combinations to effectively treat EC patients.
authors.affiliation: Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Honjo
authors.affiliation: Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jaffer A
authors.initials: JA
authors.lastname: Ajani
authors.affiliation: Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ailing W
authors.initials: AW
authors.lastname: Scott
authors.affiliation: Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Qiongrong
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Radiation Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Heath D
authors.initials: HD
authors.lastname: Skinner
authors.affiliation: Department of Gastroenterology, Hepatology and Nutrition, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: John
authors.initials: J
authors.lastname: Stroehlein
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Randy L
authors.initials: RL
authors.lastname: Johnson
authors.affiliation: Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Shumei
authors.initials: S
authors.lastname: Song
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D004357:Drug Synergism; D004938:Esophageal Neoplasms / Q000378:metabolism / Q000473:pathology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005472:Fluorouracil / Q000494:pharmacology; D064593:Heterografts; D006801:Humans; D015151:Immunoblotting; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D008687:Metformin; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D005472:Fluorouracil