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Crosstalk between Insulin/Insulin-like Growth Factor-1 Receptors and G Protein-Coupled Receptor Signaling Systems: A Novel Target for the Antidiabetic Drug Metformin in Pancreatic Cancer
Open accessAbstract
Insulin/insulin-like growth factor 1(IGF-1) receptors and G protein-coupled receptors (GPCR) signaling systems are implicated in autocrine-paracrine stimulation of a variety of malignancies, including ductal adenocarcinoma of the pancreas, one of the most lethal human diseases. Novel targets for pancreatic cancer therapy are urgently needed. We identified a crosstalk between insulin/IGF-1 receptors and GPCR signaling systems in pancreatic cancer cells, leading to enhanced signaling, DNA synthesis, and proliferation. Crosstalk between these signaling systems depends on mammalian target of rapamycin (mTOR) complex 1 (mTORC1). Metformin, the most widely used drug in the treatment of type 2 diabetes, activates AMP kinase (AMPK), which negatively regulates mTORC1. Recent results show that metformin-induced activation of AMPK disrupts crosstalk between insulin/IGF-1 receptor and GPCR signaling in pancreatic cancer cells and inhibits the growth of these cells in xenograft models. Given that insulin/IGF-1 and GPCRs are implicated in other malignancies, a similar crosstalk mechanism may be operative in other cancer cell types. Recent epidemiological studies linked administration of metformin with a reduced risk of pancreatic, breast, and prostate cancer in diabetic patients. We posit that crosstalk between insulin/IGF-1 receptor and GPCR signaling is a mechanism for promoting the development of certain types of cancer and a target for the prevention and therapy of these diseases via metformin administration. Clin Cancer Res; 16(9); 2505–11. ©2010 AACR.
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“Prior studies with KRAS G12C , RAF, and MEK inhibitors indicated that blockade of KRAS-dependent signaling activated a transcriptional program suppressing DUSP , SPRY , and ETV family genes which cooperate to mediate increased signaling flux though RTK, SOS, and MEK/ERK family members resulting in conditional bypass dependence on KRAS [4, 32-34].”
From Anti-tumor efficacy of a potent and selective non-covalent KRASG12D inhibitor (2022) · cites this paper as [32]
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Metadata
- Authors
- Rozengurt, E., Sinnett-Smith, J., & Kisfalvi, K.
- Affiliations
- University of California, Los Angeles (US)
- Authors' Affiliation: Division of Digestive Diseases, Department of Medicine, CURE: Digestive Diseases Research Center, David Geffen School of Medicine and Molecular Biology Institute, University of California at Los Angeles, Los Angeles California
- Corresponding author
- Rozengurt, Enrique
- ORCID
- Rozengurt, Enrique
- Venue
- Clinical Cancer Research
- Published
- 2010-04-28
- Volume
- 16
- Issue
- 9
- Pages
- 2505-2511
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC2862089
- OpenAlex
- W2158170204
- Cited by
- 247
- References
- 64
- Citations by year
- 2026: 2 · 2025: 10 · 2024: 9 · 2023: 8 · 2022: 12 · 2021: 9 · 2020: 13 · 2019: 12 · 2018: 9 · 2017: 19 · 2016: 20 · 2015: 20 · 2014: 21 · 2013: 30 · 2012: 23
- FWCI
- 10.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R21CA137292)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK56930, P30 DK 41301, R0-1 DK55003, R01DK056930, P30DK041301, R01DK055003)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- metformin, G protein-coupled receptors, pancreatic cancer, mTORC1, AMPK, autocrine and paracrine signaling, cell proliferation, cancer prevention, drug repurposing
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Animals, Clinical Trials as Topic, Diabetes Mellitus, Type 2, Humans, Hypoglycemic Agents, Metformin, Models, Biological, Pancreatic Neoplasms, Proteins, Receptor, Insulin, Transcription Factors, Signal Transduction, Receptor, IGF Type 1, Receptor Cross-Talk, Receptors, G-Protein-Coupled, Multiprotein Complexes, TOR Serine-Threonine Kinases
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