Metformin sensitizes chemotherapy by targeting cancer stem cells and the mTOR pathway in esophageal cancer

Honjo,Soichiro; Ajani,Jaffer  A.; Scott,Ailing  W.; Chen,Qiongrong; Skinner,Heath   D.; Stroehlein,John; Johnson,Randy L.; Song,Shumei

doi:10.3892/ijo.2014.2450

Metformin sensitizes chemotherapy by targeting cancer stem cells and the mTOR pathway in esophageal cancer

Authors:
- Soichiro Honjo
- Jaffer A. Ajani
- Ailing W. Scott
- Qiongrong Chen
- Heath D. Skinner
- John Stroehlein
- Randy L. Johnson
- Shumei Song
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Affiliations: Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA, Department of Radiation Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA, Department of Gastroenterology, Hepatology and Nutrition, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA, Department of Biochemistry and Molecular Biology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
Published online on: May 21, 2014 https://doi.org/10.3892/ijo.2014.2450
Pages: 567-574

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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.

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