title: 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.affiliation: From the Departments of Veterinary Physiology and Pharmacology and.
authors.forename: Vijayalekshmi
authors.initials: V
authors.lastname: Nair
authors.affiliation: From the Departments of Veterinary Physiology and Pharmacology and.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Sreevalsan
authors.affiliation: the Cancer Research Institute, M.D. Anderson Cancer Center-Orlando, Orlando, Florida 32806, the Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Riyaz
authors.initials: R
authors.lastname: Basha
authors.affiliation: the Cancer Research Institute, M.D. Anderson Cancer Center-Orlando, Orlando, Florida 32806, the Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Maen
authors.initials: M
authors.lastname: Abdelrahim
authors.affiliation: the Department of Emergency Medicine, M.D. Anderson Cancer Center, Houston, Texas 77030, and.
authors.forename: Ala
authors.initials: A
authors.lastname: Abudayyeh
authors.affiliation: Veterinary Pathobiology, Texas A&M University, College Station, Texas 77843.
authors.forename: Aline
authors.initials: A
authors.lastname: Rodrigues Hoffman
authors.affiliation: From the Departments of Veterinary Physiology and Pharmacology and the Institute of Biosciences and Technology, Texas A&M Health Sciences Center, Houston, Texas 77030 ssafe@cvm.tamu.edu.
authors.forename: Stephen
authors.initials: S
authors.lastname: Safe
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D051703:Sp Transcription Factors / Q000235:genetics* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051703:Sp Transcription Factors; D008687:Metformin; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins
keywords: Epidermal Growth Factor Receptor (EGFR); Gene Expression; IGFR Down-regulation; Insulin-like Growth Factor (IGF); Metformin; Pancreatic Cancer; Ras Inhibition; Sp Transcription Factors; Specificity Protein 1 (Sp1); mTOR Down-regulation