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
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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.
“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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BackgroundLiu, B., Fan, Z., Edgerton, S. M., Yang, X., Lind, S. E., & Thor, A. D. (2011) · Cell Cycle · doi:10.4161/cc.10.17.16359 · Cited by 146 · see citing works
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Mohammed, A., Janakiram, N. B., Brewer, M., Ritchie, R. L., Marya, A., Lightfoot, S., Steele, V. E., & Rao, C. V. (2013) · Translational Oncology · doi:10.1593/tlo.13556 · Cited by 142 · see citing works
“Our observation is consistent with other recent reports in which metformin disrupts mTOR, IGF-1, and CSC signaling pathways and prevents tumor growth [8,12,13,16,17,31,32,38].”
BackgroundResultMetabolic Roles of AMPK and Metformin in Cancer Cells
Choi, Y. K., & Park, K. (2013) · Molecules and Cells · doi:10.1007/s10059-013-0169-8 · Cited by 143 · see citing works
“Crosstalk between insulin/IGF-1 receptors and G-protein-coupled receptor signaling, implicated in autocrine-paracrine stimulation of a variety of malignancies, is also disrupted by metformininduced AMPK activation, leading to attenuated DNA synthesis and proliferation (Rozengurt et al., 2010).”
BackgroundDiabetes and Pancreatic Cancer: Chicken or Egg?
Magruder, J. T., Elahi, D., & Andersen, D. K. (2011) · Pancreas · doi:10.1097/mpa.0b013e318209e05d · Cited by 140 · see citing works
“Detailed reviews of these mechanisms are provided by Pollak74 and Rosengurt et al.75 Metformin activates the liver kinase B1 (LKB1)-adenosine monophosphate protein-activated kinase (AMPK) pathway, which serves not only to enhance cellular energy production (thereby reducing the need for insulin-mediated glucose transp…”
BackgroundRozengurt, E., Sinnett‐Smith, J. W., & Eibl, G. (2018) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-017-0005-2 · Cited by 135 · see citing works
Self-citationPancreatitis-Diabetes-Pancreatic Cancer
Andersen, D. K., Andrén‐Sandberg, Å., Duell, E. J., Goggins, M., Korc, M., Petersen, G. M., Smith, J. P., & Whitcomb, D. C. (2013) · Pancreas · doi:10.1097/mpa.0b013e3182a9ad9d · Cited by 132 · see citing works
Nair, V., Sreevalsan, S., Basha, R., Abdelrahim, M., Abudayyeh, A., Rodrigues Hoffman, A., & Safe, S. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.592576 · Cited by 129 · see citing works
“The potential clinical applications for metformin in cancer chemotherapy also stems from reports on the anticancer activities of this drug in cancer cells in culture and in in vivo models (1-4,13-28).”
BackgroundInfluentialSoares, H. P., Ni, Y., Kisfalvi, K., Sinnett‐Smith, J. W., & Rozengurt, E. (2013) · PLoS ONE · doi:10.1371/journal.pone.0057289 · Cited by 124 · see citing works
“Then, the cultures were stimulated with a combination of insulin (10 ng/ ml) and the GPCR agonist neurotensin (5 nM) for 2 h to elicit positive crosstalk [18,20].”
MethodSelf-citationDefining the pathway to insulin-like growth factor system targeting in cancer
Rosenzweig, S. A., & Atreya, H. S. (2010) · Biochemical Pharmacology · doi:10.1016/j.bcp.2010.06.013 · Cited by 127 · see citing works
“Additional, novel targeting opportunities exist based on crosstalk that occurs between IGF-1Rs and EGFRs [99], VEGFRs [100] and highly druggable GPCRs [101].”
BackgroundAl-Mrabeh, A., Hollingsworth, K. G., Shaw, J. A. M., McConnachie, A., Sattar, N., Lean, M. E. J., & Taylor, R. (2020) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(20)30303-x · Cited by 122 · see citing works
mIGF‐1/JNK1/SirT1 signaling confers protection against oxidative stress in the heart
Vinciguerra, M., Santini, M. P., Martínez, C., Pazienza, V., Claycomb, W. C., Giuliani, A., & Rosenthal, N. A. (2011) · Aging Cell · doi:10.1111/j.1474-9726.2011.00766.x · Cited by 122 · see citing works
“We cannot exclude the possibility that IGF-1 and ⁄ or mIGF-1 could cross talk with G-protein-coupled receptor–dependent signaling (Rozengurt et al., 2010).”
BackgroundAcquired resistance to drugs targeting receptor tyrosine kinases
Rosenzweig, S. A. (2011) · Biochemical Pharmacology · doi:10.1016/j.bcp.2011.12.025 · Cited by 122 · see citing works
“IGF-1Rs have been found to be downstream of RTKs [53] and G-protein coupled receptors with crosstalk occurring at the receptor level, as well as via downstream effectors [54].”
BackgroundTargeting cancer cell metabolism in pancreatic adenocarcinoma
Cohen, R., Neuzillet, C., Tijeras‐Raballand, A., Faivre, S. J., Gramont, A. D. E., & Raymond, É. (2015) · Oncotarget · doi:10.18632/oncotarget.4160 · Cited by 119 · see citing works
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Targeting LKB1 signaling in cancer
Korsse, S. E., Peppelenbosch, M. P., & van Veelen, W. (2012) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2012.12.006 · Cited by 107 · see citing works
“The anti-proliferative effects have been shown to be mediated via inhibition of insulin-like growth factor-1 (IGF-1) signaling [149–152], but also via suppression of genes inducing cell cycle S- and M-phases [153–155].”
BackgroundSinnett‐Smith, J. W., Kisfalvi, K., Kui, R. K., & Rozengurt, E. (2012) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2012.11.010 · Cited by 106 · see citing works
“Other studies showed that metformin inhibited the proliferation of breast, colon, lung and prostate cancer cells [10, 19].”
BackgroundMethodInfluentialSelf-citationInhibition of Mutant GNAQ Signaling in Uveal Melanoma Induces AMPK-Dependent Autophagic Cell Death
Ambrosini, G., Musi, E., Ho, A. L., de Stanchina, E., & Schwartz, G. K. (2013) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-12-1020 · Cited by 101 · see citing works
Insulin-like growth factor-I regulates GPER expression and function in cancer cells
Marco, P. D., Bartella, V., Vivacqua, A., Lappano, R., Santolla, M. F., Morcavallo, A., Pezzi, V., Belfiore, A., & Maggiolini, M. (2012) · Oncogene · doi:10.1038/onc.2012.97 · Cited by 101 · see citing works
Profiles of Circulating miRNAs Following Metformin Treatment in Patients with Type 2 Diabetes
Demirsoy, İ. H., Ertural, D. Y., Balcı, Ş., Çınkır, Ü., Sezer, K., Tamer, L., & Aras, N. (2018) · Journal of Medical Biochemistry · doi:10.2478/jomb-2018-0009 · Cited by 98 · see citing works
Soares, H. P., Ming, M., Mellon, M., Young, S. H., Han, L., Sinnet-Smith, J., & Rozengurt, E. (2015) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-14-0669 · Cited by 97 · see citing works
Self-citationRepurposing phenformin for the targeting of glioma stem cells and the treatment of glioblastoma
Jiang, W., Finniss, S., Cazacu, S., Xiang, C., Brodie, Z., Mikkelsen, T., Poisson, L., Shackelford, D. B., & Brodie, C. (2016) · Oncotarget · doi:10.18632/oncotarget.10919 · Cited by 95 · see citing works
Role of bile acids in carcinogenesis of pancreatic cancer: An old topic with new perspective
Feng, H., & Chen, Y. (2016) · World Journal of Gastroenterology · doi:10.3748/wjg.v22.i33.7463 · Cited by 94 · see citing works
Acquired Resistance to Drugs Targeting Tyrosine Kinases
Rosenzweig, S. A. (2018) · Advances in cancer research · doi:10.1016/bs.acr.2018.02.003 · Cited by 93 · see citing works
The complexities of obesity and diabetes with the development and progression of pancreatic cancer
Bao, B., Wang, Z., Li, Y., Kong, D., Ali, S. S., Banerjee, S., Ahmad, A., & Sarkar, F. H. (2010) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2010.11.003 · Cited by 94 · see citing works
“Additional evidence showed that metformin can inhibit PC cell growth and proliferation by disruption of insulin/IGF-1R and GPCR crosstalk through the activation of AMPK [189,191].”
BackgroundInfluentialEnvironmental risk factors for pancreatic cancer: an update
Barone, E., Corrado, A., Gemignani, F., & Landi, S. (2016) · Archives of Toxicology · doi:10.1007/s00204-016-1821-9 · Cited by 93 · see citing works
Association Between Metformin Use and Risk of Prostate Cancer and Its Grade
Margel, D., Urbach, D. R., Lipscombe, L. L., Bell, C. M., Kulkarni, G. S., Austin, P. C., & Fleshner, N. E. (2013) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djt170 · Cited by 91 · see citing works
Cross-talk between GPER and growth factor signaling
Lappano, R., Marco, P. D., Francesco, E. M. D., Chimento, A., Pezzi, V., & Maggiolini, M. (2013) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2013.03.005 · Cited by 90 · see citing works
The role of insulin and IGF system in pancreatic cancer
Trajkovic‐Arsic, M., Kalideris, E., & Siveke, J. T. (2013) · Journal of Molecular Endocrinology · doi:10.1530/jme-12-0259 · Cited by 90 · see citing works
“It has also been shown that IR shows cross talk with G-protein-coupled receptors and further activates mTOR signaling and stimulates DNA synthesis and proliferation of cancer cells in PDAC (Rozengurt et al. 2010).”
BackgroundDrugging IGF-1R in cancer: New insights and emerging opportunities
Wang, P., Mak, V. C. Y., & Cheung, L. W. T. (2022) · Genes & Diseases · doi:10.1016/j.gendis.2022.03.002 · Cited by 88 · see citing works
KRAS, YAP, and obesity in pancreatic cancer: A signaling network with multiple loops
Eibl, G., & Rozengurt, E. (2017) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2017.10.007 · Cited by 87 · see citing works
Self-citationMetformin Inhibits the Growth of Human Pancreatic Cancer Xenografts
Kisfalvi, K., Moro, A., Sinnett‐Smith, J. W., Eibl, G., & Rozengurt, E. (2013) · Pancreas · doi:10.1097/mpa.0b013e31827aec40 · Cited by 86 · see citing works
“Crosstalk between insulin/IGF receptor and GPCR signaling systems is mediated through the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR complex 1 (mTORC1) signaling module,(18) a key pathway in insulin/IGF action(19) and pancreatic cancer proliferation.(20) Metformin (1,1-dimethylbiguanide hydrochloride) is the most w…”
BackgroundSelf-citationMetformin in therapeutic applications in human diseases: its mechanism of action and clinical study
Du, Y., Zhu, Y., Zhou, Y., Ding, J., & Liu, J. (2022) · Molecular Biomedicine · doi:10.1186/s43556-022-00108-w · Cited by 82 · see citing works
Mitochondrial Metabolism in PDAC: From Better Knowledge to New Targeting Strategies
Reyes‐Castellanos, G., Masoud, R., & Carrier, A. (2020) · Biomedicines · doi:10.3390/biomedicines8080270 · Cited by 82 · see citing works
The Role of Gastrin and CCK Receptors in Pancreatic Cancer and other Malignancies
Smith, J. P., Fonkoua, L. A. K., & Moody, T. W. (2016) · International Journal of Biological Sciences · doi:10.7150/ijbs.14952 · Cited by 78 · see citing works
“G-protein coupled receptors (GPCRs) like the CCK receptors have been demonstrated to modulate growth of gastrointestinal cancers [68, 69].”
BackgroundLaw, N. C., White, M. F., & Hunzicker-Dunn, M. E. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.763235 · Cited by 79 · see citing works
“However, the mechanism by which GPCRs activate the PI3K/AKT pathway, either alone or in conjunction with RTKs, is poorly understood (3, 10).”
Ming, M., Sinnett‐Smith, J. W., Wang, J., Soares, H. P., Young, S. H., Eibl, G., & Rozengurt, E. (2014) · PLoS ONE · doi:10.1371/journal.pone.0114573 · Cited by 77 · see citing works
“The activation of the PI3K/Akt/mTORC1 and MEK/ERK pathways plays a pivotal role in stimulating DNA synthesis, cell cycle progression and proliferation of PDAC cells and are negatively regulated by AMPK [21].”
BackgroundSelf-citationMetformin suppresses cancer cell growth in endometrial carcinoma by inhibiting PD-L1
Xue, J., Li, L., Li, N., Li, F., Qin, X., Li, T., & Liu, M. (2019) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2019.172541 · Cited by 77 · see citing works
Insulin-like Growth Factor: Current Concepts and New Developments in Cancer Therapy
King, E. R., & Wong, K. (2011) · Recent Patents on Anti-Cancer Drug Discovery · doi:10.2174/157489212798357930 · Cited by 77 · see citing works
Krishan, S., Richardson, D. R., & Sahni, S. (2014) · Molecular Pharmacology · doi:10.1124/mol.114.095810 · Cited by 77 · see citing works
“of apoptosis, and reduced migration and invasion in a variety of human cancer cell lines (Papanas et al., 2010; Rozengurt et al., 2010; Liu et al., 2011; Viollet et al., 2012).”
BackgroundChai, X.-Q., Chu, H., Yang, X., Meng, Y.-P., Shi, P., & Gou, S. (2015) · Scientific Reports · doi:10.1038/srep14404 · Cited by 74 · see citing works
Obesity and Pancreatic Cancer: Insight into Mechanisms
Eibl, G., & Rozengurt, E. (2021) · Cancers · doi:10.3390/cancers13205067 · Cited by 72 · see citing works
Self-citationMetformin as an antitumor agent in cancer prevention and treatment
Li, D. (2011) · Journal of Diabetes · doi:10.1111/j.1753-0407.2011.00119.x · Cited by 68 · see citing works
“The growth inhibition was found to be related to increased phosphorylation of AMPK and reduced expression of fatty acid synthase.40,41 Metformin inhibited the growth of human pancreatic cancer cells xenografted into nude mice by disrupting the cross-talk between IR and G-protein-coupled receptors (GPCR) through activa…”
BackgroundTherapeutic strategies targeting cancer stem cells
Ning, X., Shu, J., Du, Y., Ben, Q., & Li, Z. (2013) · Cancer Biology & Therapy · doi:10.4161/cbt.23622 · Cited by 68 · see citing works
“It has been showed that in vivo and in vitro metformin can inhibit cancer cell growth of breast cancer,(24-26) ovarian cancer,(27) endometrial cancer,(28) prostate cancer(29,30) and pancreatic cancer.(31) Chemotherapy-resistant ovarian cancer cells can also be killed by metformin.”
BackgroundInsulin Receptor and GPCR Crosstalk Stimulates YAP via PI3K and PKD in Pancreatic Cancer Cells
Fang, H., Xu, Q., Zhao, Y., Stevens, J. V., Young, S. H., Sinnett‐Smith, J. W., & Rozengurt, E. (2017) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-17-0023 · Cited by 68 · see citing works
Self-citationDiabetes, pancreatic cancer, and metformin therapy
Gong, J., Robbins, L., Lugea, A., Waldron, R. T., Jeon, C. Y., & Pandol, S. J. (2014) · Frontiers in Physiology · doi:10.3389/fphys.2014.00426 · Cited by 67 · see citing works
“AMPK activation leads to disruption of insulin/IGF-1 signaling through inhibition of mammalian target of rapamycin (mTOR, Rozengurt et al., 2010).”
BackgroundJian‐Yu, E., Graber, J. M., Lu, S., Lin, Y., Lu‐Yao, G. L., & Tan, X. (2017) · Current Medicinal Chemistry · doi:10.2174/0929867324666170412145232 · Cited by 67 · see citing works
“Interestingly, metformin has been shown to inhibit pancreatic cancer growth by disrupting the crosstalk between insulin/insulin growth factor 1 (IGF-1) receptor and G proteincoupled receptors (GPCR) [31].”
BackgroundÖzkan, E. E. (2011) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2011.07.002 · Cited by 67 · see citing works
Personalized therapy in endometrial cancer: Challenges and opportunities
Westin, S. N., & Broaddus, R. R. (2012) · Cancer Biology & Therapy · doi:10.4161/cbt.13.1.18438 · Cited by 66 · see citing works
“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 · see citing works
“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 · see citing works
Chaudhary, S. C., Kurundkar, D., Elmets, C. A., Kopelovich, L., & Athar, M. (2012) · Photochemistry and Photobiology · doi:10.1111/j.1751-1097.2012.01165.x · Cited by 64 · see citing works
Rozengurt, E. (2014) · Frontiers in Physiology · doi:10.3389/fphys.2014.00357 · Cited by 64 · see citing works
“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).”
BackgroundSelf-citationMetformin-induced anticancer activities: recent insights
Safe, S. H., Nair, V., & Karki, K. (2017) · Biological Chemistry · doi:10.1515/hsz-2017-0271 · Cited by 61 · see citing works
“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 · see citing works
Self-citationDiabetes and pancreatic cancer survival: a prospective cohort-based study
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 59 · see citing works
“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 57 · see citing works
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 56 · see citing works
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 55 · see citing works
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 · see citing works
Marco, P. D., Cirillo, F., Vivacqua, A., Malaguarnera, R., Belfiore, A., & Maggiolini, M. (2015) · Frontiers in Endocrinology · doi:10.3389/fendo.2015.00030 · Cited by 54 · see citing works
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Diabetes mellitus carries a risk of gastric cancer: A meta-analysis
Shimoyama, S. (2013) · World Journal of Gastroenterology · doi:10.3748/wjg.v19.i40.6902 · Cited by 53 · see citing works
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 · see citing works
Pancreatic endocrine and exocrine signaling and crosstalk in physiological and pathological status
Hu, C., Chen, Y., Yin, X., Xu, R., Yin, C., Wang, C., & Zhao, Y. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02098-3 · Cited by 59 · see citing works
Cancer Risk in Type 2 Diabetes Mellitus: Metabolic Links and Therapeutic Considerations
Sun, G. E. C., & Kashyap, S. R. (2011) · Journal of Nutrition and Metabolism · doi:10.1155/2011/708183 · Cited by 51 · see citing works
“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 50 · see citing works
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Metformin: review of epidemiology and mechanisms of action in pancreatic cancer
Eibl, G., & Rozengurt, E. (2021) · Cancer and Metastasis Reviews · doi:10.1007/s10555-021-09977-z · Cited by 49 · see citing works
Self-citationGarofalo, C., Capristo, M., Manara, M. C., Mancarella, C., Landuzzi, L., Belfiore, A., Lollini, P., Picci, P., & Scotlandi, K. (2013) · PLoS ONE · doi:10.1371/journal.pone.0083832 · Cited by 49 · see citing works
“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 · see citing works
Krieger, C. C., Perry, J. D., Morgan, S. J., Kahaly, G. J., & Gershengorn, M. C. (2017) · Endocrinology · doi:10.1210/en.2017-00528 · Cited by 48 · see citing works
Targeting mTOR in Pancreatic Ductal Adenocarcinoma
Iriana, S., Ahmed, S., Gong, J., Annamalai, A., Tuli, R., & Hendifar, A. E. (2016) · Frontiers in Oncology · doi:10.3389/fonc.2016.00099 · Cited by 46 · see citing works
Park, J., Lee, J. H., Park, Y., Park, S. J., Cheon, J. H., Kim, W. H., & Kim, T. I. (2017) · World Journal of Gastroenterology · doi:10.3748/wjg.v23.i28.5196 · Cited by 47 · see citing works
Targeting TORC1/2 Enhances Sensitivity to EGFR Inhibitors in Head and Neck Cancer Preclinical Models
Cassell, A., Freilino, M. L., Lee, J., Barr, S. M., Wang, L., Panahandeh, M. C., Thomas, S. M., & Grandis, J. R. (2012) · Neoplasia · doi:10.1593/neo.121212 · Cited by 46 · see citing works
“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].”
BackgroundMonteagudo, S., Pérez‐Martínez, F. C., Pérez‐Carrión, M. D., Guerra, J., Merino, S., Sánchez‐Verdú, P., & Ceña, V. (2011) · Nanomedicine · doi:10.2217/nnm.11.61 · Cited by 46 · see citing works
IGF-1R targeting in cancer – does sub-cellular localization matter?
Soni, U. K., Jenny, L., & Hegde, R. S. (2023) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-023-02850-7 · Cited by 45 · see citing works
“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
Bahado-Singh, R. O., Poon, L. C., Yılmaz, A., Syngelaki, A., Türkoğlu, O., Kumar, P., Kirma, J., Allos, M., Accurti, V., Li, J., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-15882-9 · Cited by 45 · see citing works
Pancreatic cancer: molecular pathogenesis and emerging therapeutic strategies
Rozengurt, E., & Eibl, G. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02499-y · Cited by 45 · see citing works
Self-citationLee, J., Hong, E. M., Kim, J. H., Jung, J. H., Park, S. W., Koh, D. H., Choi, M. H., Jang, H. J., & Kae, S. H. (2019) · Journal of Cancer · doi:10.7150/jca.26380 · Cited by 44 · see citing works
“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
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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