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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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Personalized therapy in endometrial cancer: Challenges and opportunities
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“Due to the known activation of the IGF-IR pathway with inhibition of mTOR, there exists a rationale for combination of IGF-IR inhibitors and drugs targeting mTOR.(72) There are several IGF-IR inhibitors in clinical investigation, including IMC-A12, AMG479, H10H5, and OSI-906.”
BackgroundRole of protein kinase D signaling in pancreatic cancer
Guha, S., Tanasanvimon, S., Sinnett‐Smith, J. W., & Rozengurt, E. (2010) · Biochemical Pharmacology · doi:10.1016/j.bcp.2010.07.002 · Cited by 64
“This function of PKD could be relevant to PDAC given the growth-promoting effect of increased insulin secretion from b cells on epithelial acinar and ductal pancreatic cells [91].”
BackgroundSelf-citationClinical Outcomes of Chemotherapy for Diabetic and Nondiabetic Patients With Pancreatic Cancer
Nakai, Y., Isayama, H., Sasaki, T., Mizuno, S., Sasahira, N., Kogure, H., Kawakubo, K., Yamamoto, N., Hirano, K., Ijichi, H., et al. (2012) · Pancreas · doi:10.1097/mpa.0b013e31825de678 · Cited by 64
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“As shown in Figure 2, PLCβ produces second messengers that activate members of the protein kinase C (PKC) family which, in turn, phosphorylate and activate the protein kinases of the protein kinase D (PKD) family, including PKD1, PKD2, and PKD3 (Rozengurt et al., 2005).”
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“Metformin and related biquanides are highly effective anticancer agents in pancreatic cancer cells (Kisfalvi et al., 2009; Rozengurt et al., 2010; Kim et al., 2011; Bao et al., 2012; Gou et al., 2013; Karnevi et al., 2013; Lonardo et al., 2013; Sinnett-Smith et al., 2013; Soares et al., 2013; Li et al., 2017; Rajeshku…”
BackgroundHao, F., Xu, Q., Wang, J., Yu, S., Chang, H.-H., Sinnett-Smith, J., Eibl, G., & Rozengurt, E. (2019) · PLOS ONE · doi:10.1371/journal.pone.0216603 · Cited by 55
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Toriola, A. T., Stolzenberg‐Solomon, R. Z., Dalidowitz, L., Linehan, D. C., & Colditz, G. A. (2014) · British Journal of Cancer · doi:10.1038/bjc.2014.224 · Cited by 60
“Metformin, an anti-diabetic drug, has been shown to improve survival among pancreatic cancer patients (Sadeghi et al, 2012), possibly via its impact on insulin/IGF-I signalling (Rozengurt et al, 2010).”
BackgroundTang, Y., Zhu, L., Yu, L., Yu, J., Wang, J., Zeng, X., Hu, K.-X., Liu, J., & Xu, J. (2017) · BioMed Research International · doi:10.1155/2017/5905384 · Cited by 60
Molecular targets of metformin antitumor action
Sośnicki, S., Kapral, M., & Węglarz, L. (2016) · Pharmacological Reports · doi:10.1016/j.pharep.2016.04.021 · Cited by 57
The Role of Nutraceuticals in Pancreatic Cancer Prevention and Therapy
Li, Y., Go, V. L. W., & Sarkar, F. H. (2014) · Pancreas · doi:10.1097/mpa.0000000000000257 · Cited by 56
Arrestin-β-1 Physically Scaffolds TSH and IGF1 Receptors to Enable Crosstalk
Krieger, C. C., Boutin, A., Jang, D., Morgan, S. J., Banga, J. P., Kahaly, G. J., Kłubo-Gwieździńska, J., Neumann, S., & Gershengorn, M. C. (2019) · Endocrinology · doi:10.1210/en.2019-00055 · Cited by 55
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Revisiting the Relationship Between Blood Pressure and Insulin-Like Growth Factor-1
Schutte, A. E., Volpe, M., Tocci, G., & Conti, E. (2014) · Hypertension · doi:10.1161/hypertensionaha.113.03057 · Cited by 52
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Cancer Risk in Type 2 Diabetes Mellitus: Metabolic Links and Therapeutic Considerations
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“The activation of AMPK reprograms cellular metabolism by acting on mTORC1, p53, fatty acid synthase, and other molecules involved with regulating cell growth and metabolism [106].”
BackgroundPancreatic cancer and diabetes: A two-way relationship in the perspective of diabetologist
Salvatore, T., Marfella, R., Rizzo, M. R., & Sasso, F. C. (2015) · International Journal of Surgery · doi:10.1016/j.ijsu.2015.06.063 · Cited by 51
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Metformin: review of epidemiology and mechanisms of action in pancreatic cancer
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“shows potential advantages with respect to other mTOR inhibitors, such as rapamycin [51,52].”
BackgroundThe bidirectional interation between pancreatic cancer and diabetes
Li, J., Cao, G., Ma, Q., Liu, H., Li, W., & Han, L. (2012) · World Journal of Surgical Oncology · doi:10.1186/1477-7819-10-171 · Cited by 49
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Targeting mTOR in Pancreatic Ductal Adenocarcinoma
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Targeting TORC1/2 Enhances Sensitivity to EGFR Inhibitors in Head and Neck Cancer Preclinical Models
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“Mammalian target of rapamycin (mTOR) is activated by both EGFRdependent and EGFR-independent pathways, including G protein– coupled receptors, and has been implicated as a potential therapeutic target in several solid tumors including HNSCC [9,12,13].”
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“And finally, crosstalk between IGF-1R and G-protein coupled receptor (GPCR) signaling pathways is mediated by their convergence upon mTORC1 activation [13].”
BackgroundIntegrated Proteomic and Metabolomic prediction of Term Preeclampsia
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“In pancreatic cancer, metformin has been shown to inhibit the growth of human cancer cells in a xenograft mouse model through a mechanism of disrupted cross-talk between the insulin receptor and a G-protein–coupled receptor [31, 32].”
Background
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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