期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 289, 期 40, 页码 27692-27701出版社
ELSEVIER
DOI: 10.1074/jbc.M114.592576
关键词
Epidermal Growth Factor Receptor (EGFR); Gene Expression; Insulin-like Growth Factor (IGF); Pancreatic Cancer; Specificity Protein 1 (Sp1); IGFR Down-regulation; Ras Inhibition; Sp Transcription Factors; mTOR Down-regulation; Metformin
资金
- National Institutes of Health [R01CA136571, P30ES023512]
- Texas AgriLife Research
Background: Metformin inhibits pancreatic cancer cell and tumor growth and down-regulated Sp transcription factors. Results: Inhibition of mTOR and Ras signaling by metformin is due to decreased expression of Sp-regulated insulin-like growth factor-1 receptor (IGF-1R) and epidermal growth factor receptor (EGFR), respectively. Conclusion: Metformin-induced down-regulation of Sp proteins affects multiple pro-oncogenic pathways. Significance: These results identify important metformin-induced anticancer activities. 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.
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