The DOI matches its Crossref record; 50 of the 51 references it cites were found in a registry or an index.
Mechanism of Metformin-dependent Inhibition of Mammalian Target of Rapamycin (mTOR) and Ras Activity in Pancreatic Cancer
Open accessAbstract
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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“inhibition of mTOR (Kickstein et al., 2010; Nair et al., 2014; Pérez-Revuelta et al., 2014)”
From Metformin as a tool to target aging (2016) · cites this paper as Nair et al., 2014
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“However, many in vitro studies have used mM concentrations of metformin to demonstrate an anti-proliferative action in tumor cells in culture [see (114, 115); Table 2].”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [114]
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“In conclusion, since beneficial effects of metformin are not seen in all cancers further studies are required to determine whether the anti-cancer actions are direct or are secondary to the positive effects of metformin on healthspan that are apparent in obese patients such as improved glucose homeostasis, enhanced insulin sensitivity and reduced signaling through the IGF-1–mTOR pathway (114, 242)”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [114]
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1 retracted
Activation of the AMP-activated Protein Kinase by the Anti-diabetic Drug Metformin in Vivo
Zou, M., Kirkpatrick, S. S., Davis, B. J., Nelson, J. S., Wiles, W. G., Schlattner, U., Neumann, D., Brownlee, M., Freeman, M. B., & Goldman, M. H. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m404421200 · Cited by 480
RetractedMetformin and reduced risk of cancer in diabetic patients
Evans, J. M. M., Donnelly, L. A., Emslie-Smith, A. M., Alessi, D. R., & Morris, A. D. (2005) · BMJ · doi:10.1136/bmj.38415.708634.f7 · Cited by 2,388
The Kinase LKB1 Mediates Glucose Homeostasis in Liver and Therapeutic Effects of Metformin
Shaw, R. J., Lamia, K. A., Vasquez, D., Koo, S.-H., Bardeesy, N., DePinho, R. A., Montminy, M., & Cantley, L. C. (2005) · Science · doi:10.1126/science.1120781 · Cited by 1,950
SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth
Porstmann, T., Santos, C. R., Griffiths, B., Cully, M., Wu, M., Leevers, S., Griffiths, J. R., Chung, Y.-L., & Schulze, A. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.07.007 · Cited by 1,413
New Users of Metformin Are at Low Risk of Incident Cancer
Libby, G., Donnelly, L. A., Donnan, P. T., Alessi, D. R., Morris, A. D., & Evans, J. M. M. (2009) · Diabetes Care · doi:10.2337/dc08-2175 · Cited by 996
Buzzai, M., Jones, R. G., Amaravadi, R. K., Lum, J. J., DeBerardinis, R. J., Zhao, F., Viollet, B., & Thompson, C. B. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-4447 · Cited by 949
Jiralerspong, S., Palla, S. L., Giordano, S. H., Meric-Bernstam, F., Liedtke, C., Barnett, C. M., Hsu, L., Hung, M.-C., Hortobagyi, G. N., & Gonzalez-Angulo, A. M. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2009.19.6410 · Cited by 880
Sahra, I. B., Laurent, K., Loubat, A., Giorgetti-Peraldi, S., Colosetti, P., Auberger, P., Tanti, J. F., Le Marchand-Brustel, Y., & Bost, F. (2008) · Oncogene · doi:10.1038/sj.onc.1211024 · Cited by 861
Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1
Ben Sahra, I., Regazzetti, C., Robert, G., Laurent, K., Le Marchand-Brustel, Y., Auberger, P., Tanti, J.-F., Giorgetti-Peraldi, S., & Bost, F. (2011) · Cancer Research · doi:10.1158/0008-5472.can-10-1769 · Cited by 616
EGF Receptor is Required for KRAS-induced Pancreatic Tumorigenesis
Ardito, C. M., Grüner, B., Takeuchi, K. K., Lubeseder-Martellato, C., Teichmann, N., Mazur, P., DelGiorno, K. E., Carpenter, E. S., Halbrook, C., Hall, J. C., et al. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.07.024 · Cited by 522
Cited by
Sorted by citations
Metformin as a tool to target aging
Barzilai, N., Crandall, J. P., Kritchevsky, S. B., & Espeland, M. A. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.05.011 · Cited by 1,096
Aging and age‐related diseases: from mechanisms to therapeutic strategies
Li, Z., Zhang, Z., Ren, Y., Wang, Y., Fang, J., Yue, H., Ma, S., & Guan, F. (2021) · Biogerontology · doi:10.1007/s10522-021-09910-5 · Cited by 702
Madeo, F., Carmona-Gutierrez, D., Hofer, S. J., & Kroemer, G. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.01.018 · Cited by 630
Campbell, J. M., Bellman, S. M., Stephenson, M. D., & Lisy., K. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2017.08.003 · Cited by 455
Sp1 transcription factor: A long-standing target in cancer chemotherapy
Vizcaíno, C., Mansilla, S., & Portugal, J. (2015) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2015.05.008 · Cited by 377
Metadata
- Authors
- Nair, V., Sreevalsan, S., Basha, R., Abdelrahim, M., Abudayyeh, A., Rodrigues Hoffman, A., & Safe, S.
- Affiliations
- Texas A&M University (US)
- Baylor College of Medicine (US)
- The University of Texas MD Anderson Cancer Center (US)
- Texas A&M Health Science Center (US)
- Corresponding author
- Safe, Stephen
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2014-10
- Volume
- 289
- Issue
- 40
- Pages
- 27692-27701
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4183806
- OpenAlex
- W2043152532
- Cited by
- 129
- References
- 51
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 7 · 2023: 8 · 2022: 11 · 2021: 14 · 2020: 17 · 2019: 10 · 2018: 11 · 2017: 16 · 2016: 13 · 2015: 13 · 2014: 3
- FWCI
- 6.15
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (R01CA136571, P30ES023512)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Keywords
- metformin, pancreatic cancer, mTOR signaling, Ras signaling, specificity protein transcription factors, Sp1, Sp3, Sp4, IGF-1 receptor, EGFR, anticancer activity, chemoprevention, drug repurposing
- MeSH terms
- Animals, Antineoplastic Agents, Humans, Male, Metformin, Mice, Nude, Pancreatic Neoplasms, Signal Transduction, Down-Regulation, Gene Expression Regulation, Neoplastic, ras Proteins, Cell Line, Tumor, Mice, Sp Transcription Factors, TOR Serine-Threonine Kinases
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