Mechanism of metformin-dependent inhibition of mammalian target of rapamycin (mTOR) and Ras activity in pancreatic cancer: role of specificity protein (Sp) transcription factors.

Abstract

The antidiabetic drug metformin exhibits both chemopreventive and chemotherapeutic activity for multiple cancers including pancreatic cancer; however, the underlying mechanism of action of metformin is unclear. A recent study showed that metformin down-regulated specificity protein (Sp) transcription factors (TFs) Sp1, Sp3, and Sp4 in pancreatic cancer cells and tumors, and this was accompanied by down-regulation of several pro-oncogenic Sp-regulated genes. Treatment with metformin or down-regulation of Sp TFs by RNAi also inhibits two major pro-oncogenic pathways in pancreatic cancer cells, namely mammalian target of rapamycin (mTOR) signaling and epidermal growth factor (EGFR)-dependent activation of Ras. Metformin and Sp knockdown by RNAi decreased expression of the insulin-like growth factor-1 receptor (IGF-1R), resulting in inhibition of mTOR signaling. Ras activity was also decreased by metformin and Sp knockdown of EGFR, another Sp-regulated gene. Thus, the antineoplastic activities of metformin in pancreatic cancer are due, in part, to down-regulation of Sp TFs and Sp-regulated IGF-1R and EGFR, which in turn results in inhibition of mTOR and Ras signaling, respectively.

• Authors: Vijayalekshmi Nair, Sandeep Sreevalsan, Riyaz Basha, Maen Abdelrahim, Ala Abudayyeh, Aline Rodrigues Hoffman, Stephen Safe
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 289 Issue 40 Pg. 27692-701 (Oct 03 2014) ISSN: 1083-351X [Electronic] United States
• PMID: 25143389 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Antineoplastic Agents
• Sp Transcription Factors
• Metformin
• MTOR protein, human
• TOR Serine-Threonine Kinases
• ras Proteins

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Down-Regulation (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Male
• Metformin (pharmacology)
• Mice
• Mice, Nude
• Pancreatic Neoplasms (drug therapy, genetics, metabolism)
• Signal Transduction
• Sp Transcription Factors (genetics, metabolism)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, genetics, metabolism)
• ras Proteins (antagonists & inhibitors, genetics, metabolism)