The peptide-hormone glucagon-like peptide-1 activates cAMP and inhibits growth of breast cancer cells

Ligumsky, Hagai; Wolf, Ido; Israeli, Shira; Haimsohn, Michal; Ferber, Sarah; Karasik, Avraham; Kaufman, Bella; Rubinek, Tami

doi:10.1007/s10549-011-1585-0

Cited by 84 publications

(68 citation statements)

References 51 publications

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“…However, Ex-4 did not induce AMPK activation in prostate cancer cells (data not shown). Interestingly, an anti-breast cancer effect of Ex-4 has recently been reported (39). A similar mechanism by which Ex-4 attenuates cancer growth, namely the inhibition of ERK-MAPK, was confirmed by our data and a previous report (26), suggesting the importance of ERK-MAPK as a target of Ex-4 for decreasing cancer growth.…”

Section: Discussionsupporting

confidence: 91%

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Exendin-4, a GLP-1 Receptor Agonist, Attenuates Prostate Cancer Growth

et al. 2014

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Recently, pleiotropic benefits of incretin therapy beyond glycemic control have been reported. Although cancer is one of the main causes of death in diabetic patients, few reports describe the anticancer effects of incretin. Here, we examined the effect of the incretin drug exendin (Ex)-4, a GLP-1 receptor (GLP-1R) agonist, on prostate cancer. In human prostate cancer tissue obtained from patients after they had undergone radical prostatectomy, GLP-1R expression colocalized with P504S, a marker of prostate cancer. In in vitro experiments, Ex-4 significantly decreased the proliferation of the prostate cancer cell lines LNCap, PC3, and DU145, but not that of ALVA-41. This antiproliferative effect depended on GLP-1R expression. In accordance with the abundant expression of GLP-1R in LNCap cells, a GLP-1R antagonist or GLP-1R knockdown with small interfering RNA abolished the inhibitory effect of Ex-4 on cell proliferation. Although Ex-4 had no effect on either androgen receptor activation or apoptosis, it decreased extracellular signal–regulated kinase (ERK)-mitogen-activated protein kinase (MAPK) phosphorylation in LNCap cells. Importantly, Ex-4 attenuated in vivo prostate cancer growth induced by transplantation of LNCap cells into athymic mice and significantly reduced the tumor expression of P504S, Ki67, and phosphorylated ERK-MAPK. These data suggest that Ex-4 attenuates prostate cancer growth through the inhibition of ERK-MAPK activation.

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Section: Discussionsupporting

confidence: 91%

“…Thus, it can be speculated that these reports warn of a risk of carcinogenesis associated with incretin therapy. In contrast, two other studies (26,39) have demonstrated an anticancer effect of a GLP-1R agonist similar to that demonstrated in our study. Indeed, Koehler et al (26) have clearly demonstrated an anti-colon cancer effect of Ex-4.…”

Section: Discussionsupporting

confidence: 90%

Exendin-4, a GLP-1 Receptor Agonist, Attenuates Prostate Cancer Growth

et al. 2014

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“…However, exenatide inhibited proliferation and induced apoptosis in cultured murine CT26 colon cancer cells [246, 247]. …”

Section: Implications For Therapymentioning

confidence: 99%

2017 update on the relationship between diabetes and colorectal cancer: epidemiology, potential molecular mechanisms and therapeutic implications

et al. 2017

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Worldwide deaths from diabetes mellitus (DM) and colorectal cancer increased by 90% and 57%, respectively, over the past 20 years. The risk of colorectal cancer was estimated to be 27% higher in patients with type 2 DM than in non-diabetic controls. However, there are potential confounders, information from lower income countries is scarce, across the globe there is no correlation between DM prevalence and colorectal cancer incidence and the association has evolved over time, suggesting the impact of additional environmental factors. The clinical relevance of these associations depends on understanding the mechanism involved. Although evidence is limited, insulin use has been associated with increased and metformin with decreased incidence of colorectal cancer. In addition, colorectal cancer shares some cellular and molecular pathways with diabetes target organ damage, exemplified by diabetic kidney disease. These include epithelial cell injury, activation of inflammation and Wnt/β-catenin pathways and iron homeostasis defects, among others. Indeed, some drugs have undergone clinical trials for both cancer and diabetic kidney disease. Genome-wide association studies have identified diabetes-associated genes (e.g. TCF7L2) that may also contribute to colorectal cancer. We review the epidemiological evidence, potential pathophysiological mechanisms and therapeutic implications of the association between DM and colorectal cancer. Further studies should clarify the worldwide association between DM and colorectal cancer, strengthen the biological plausibility of a cause-and-effect relationship through characterization of the molecular pathways involved, search for specific molecular signatures of colorectal cancer under diabetic conditions, and eventually explore DM-specific strategies to prevent or treat colorectal cancer.

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“…At this time, only Ligumsky et al (2012) have published specific data on the relation between GLP1 receptor agonists and breast cancer.…”

Section: Breastmentioning

confidence: 99%

GLP1 and cancer: friend or foe?

Vangoitsenhoven¹,

Mathieu²,

Schueren³

2012

Endocrine-Related Cancer

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The new incretin-based therapies, dipeptidyl peptidase-4 (DPP4) inhibitors and glucagon like peptide 1 (GLP1) receptor agonists are widely used for the treatment of type 2 diabetes because of their glucose-lowering capacity with low risk of hypoglycemia. As they are weight neutral or induce weight loss in this mostly overweight population, they are popular among clinicians and patients alike. Nonetheless, concerns have been raised about GLP1's trophic effects. While increased b cell mass observed in rodents sounds appealing for treatment of diabetes, there was also an increased incidence of medullary thyroid cancer (MTC) in some species. We reviewed literature available in the Medline database until March 2012. Safety signals have emerged for MTC and pancreatic carcinoma from adverse event databases in the United States and Europe. Considering the relatively short duration of these studies, it is more likely that premalignant lesions are stimulated in presence of GLP1, rather than new neoplasms induced. Moreover, interpreting results of animal studies is difficult because of species-specific differences in presence and density of GLP1 receptors. Furthermore, data are emerging suggesting beneficial effects of GLP1 on colon and breast cancer. In conclusion, presently, the benefits of using DPP4 inhibitors or GLP1 receptor agonists for treatment of type 2 diabetes outweigh the risks. Nonetheless, their safety profile should be monitored and their indications should be widened cautiously. At present they remain contra-indicated in patients with a personal or family history of MTC or multiple endocrine neoplasia type 2.

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The peptide-hormone glucagon-like peptide-1 activates cAMP and inhibits growth of breast cancer cells

Cited by 84 publications

References 51 publications

Exendin-4, a GLP-1 Receptor Agonist, Attenuates Prostate Cancer Growth

Exendin-4, a GLP-1 Receptor Agonist, Attenuates Prostate Cancer Growth

2017 update on the relationship between diabetes and colorectal cancer: epidemiology, potential molecular mechanisms and therapeutic implications

GLP1 and cancer: friend or foe?

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