Exendin-4 — A potential therapeutic for type 2 diabetes-linked cervical cancer?

Accruing evidence suggests that type 2 diabetes (T2D) increases the risk of many cancer types and cancer-associated mortality at large. Hyperglycaemia, manifesting in relation to T2D, appears to play an important role in this trend of increased risk. In addition, co-existing inflammations might further enhance the incidence of T2D-linked cancer [[1]Chang SC Yang WV. Hyperglycemia, tumorigenesis, and chronic inflammation.Crit Rev Oncol Hematol. 2016; 108: 146-153Crossref PubMed Scopus (57) Google Scholar]. However, our understanding of the underlying mechanisms in these relationships remains poor. Uncontrolled cell proliferation is a hallmark of cancer development, which requires high protein turnover in cancer cells and involves the proteasome system [[2]Jang HH. Regulation of protein degradation by proteasomes in cancer.J Cancer Prev. 2018; 23: 153-161Crossref PubMed Google Scholar]. Notably, the proteasome system is also dysregulated in T2D [[3]Queisser MA Yao D Geisler S Hammes HP Lochnit G Schleicher ED et al.Hyperglycemia impairs proteasome function by methylglyoxal.Diabetes. 2010; 59: 670-678Crossref PubMed Scopus (128) Google Scholar], raising the possibility for it to play a potential role in T2D-linked cancer. In an article published in EBioMedicine, Mao et al show an increased co-expression of the proteasome alpha 2 subunit (PSMA2, a proteasome gene) and the glucagon-like peptide-1 receptor (GLP-1R) in cervical cancer models in T2D, which is attenuated by Exendin-4, a GLP-1R agonist [[4]Mao D Cao H Shi M Wang CC Kwong J Xi JJ et al.Increased co-expression of PSMA2 and GLP-1 receptor in cervical cancer models in type 2 diabetes attenuated by Exendin-4: a translational case-control study.EBioMedicine. 2021; 65103242Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar]. Exendin-4, which is a GLP-1 mimetic, is a new class of blood glucose-lowering drugs, which binds with GLP-1R to perform its job in T2D patients [[5]Nomiyama T Kawanami T Irie S Hamaguchi Y Terawaki Y Murase K et al.Exendin-4, a GLP-1 receptor agonist, attenuates prostate cancer growth.Diabetes. 2014; 63: 3891-3905Crossref PubMed Scopus (60) Google Scholar]. Emerging evidence suggests that this GLP-1 mimetic might also have an anti-cancer effect. For instance, a meta-analysis of randomized, controlled trials involving 63 594 patients with T2D indicated that treatment with albiglutide (a GLP-1 agonist) was associated with a 24% reduction of all sites of cancer when compared to the placebo group [[6]Cao C Yang S Zhou Z. GLP-1 receptor agonists and risk of cancer in type 2 diabetes: an updated meta-analysis of randomized controlled trials.Endocrine. 2019; 66: 157-165Crossref PubMed Scopus (13) Google Scholar]. Moreover, in prostate cancer patients, Exendin-4 has been shown to enhance the responsiveness to chemotherapy and reduce cancer growth [[7]Zhao HJ Jiang X Hu LJ Yang L Deng LD Wang YP et al.Activation of GLP-1 receptor enhances the chemosensitivity of pancreatic cancer cells.J Mol Endocrinol. 2020; 64: 103-113Crossref PubMed Scopus (2) Google Scholar]. In addition to its blood glucose-lowering effect, the GLP-1 mimetic exerts an anti-inflammatory effect on a variety of tissues and organs in the body [[8]Insuela DBR Carvalho VF. Glucagon and glucagon-like peptide-1 as novel anti-inflammatory and immunomodulatory compounds.Eur J Pharmacol. 2017; 812: 64-72Crossref PubMed Scopus (26) Google Scholar]. As inflammation plays a key role in the development of many cancer types, it is possible that this understated anti-cancer effect of the GLP-1 mimetic is linked to its anti-inflammatory effect. Of note, the GLP-1 mimetic is reported to inhibit pancreatic and breast cancer cell proliferation through the inhibition of the NF-κB pathway in experimental studies [[7]Zhao HJ Jiang X Hu LJ Yang L Deng LD Wang YP et al.Activation of GLP-1 receptor enhances the chemosensitivity of pancreatic cancer cells.J Mol Endocrinol. 2020; 64: 103-113Crossref PubMed Scopus (2) Google Scholar,[9]Iwaya C Nomiyama T Komatsu S Kawanami T Tsutsumi Y Hamaguchi Y et al.Exendin-4, a glucagonlike peptide-1 receptor agonist, attenuates breast cancer growth by inhibiting NF-κB activation.Endocrinology. 2017; 158: 4218-4232Crossref PubMed Scopus (24) Google Scholar]. In this case-control study, Mao et al. [[4]Mao D Cao H Shi M Wang CC Kwong J Xi JJ et al.Increased co-expression of PSMA2 and GLP-1 receptor in cervical cancer models in type 2 diabetes attenuated by Exendin-4: a translational case-control study.EBioMedicine. 2021; 65103242Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar] have used a combination of complementary experimental designs and approaches. This includes the exploration of the Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases for tumour-specific and normal tissue-specific expression analyses of PSMA2, expression analyses of PSMA2 and GLP-1R levels in cervical specimens from patients with and without T2D, and subsequent validation of the results in vivo using preclinical mouse models and in vitro using cervical cancer cell models. Thus, the authors provided convincing evidence to support their findings and conclusions on numerous levels. As proteasome inhibitors are approved drugs for the treatment of multiple myeloma and lymphoma, and GLP-1R agonists for the treatment of T2D, the translational potential of these research findings is high. However, a number of pertinent questions remain unanswered. For example, whether the relationship between PMSA2 and GLP-1R expression is specific to cervical cancer, or common across other T2D-related cancer types, remains unclear. Moreover, the underpinnings of why high glucose levels lead to an upregulation of PMSA2 in cancer cells and not in normal cells (a cause or a consequence of the T2D-linked cervical cancer) has not presently been investigated. The effects of high glucose levels were observed only in the CUP-1 cells (modeled murine epithelial cervical cancer cells), but not in non-cancerous mouse fibroblast and human embryonic kidney cells, which would imply these effects to be a feature of cancer cells. Thus, understanding the mechanisms involved in the effect of high glucose levels on PMSA2 expression is of clinical significance. In addition, whether the effect of Exendin-4 on reducing PSMA2 expression level in vivo is mediated indirectly through its glucose-lowering function, or directly at the tissue level, also remains unclear. In this context, it should be noted that the knockdown of GLP-1R in human and mouse cervical cancer cell lines led to the corresponding downregulation of PSMA2, implying a direct effect, independent of the glucose-lowering function of Exendin-4. Moving forward, it will be important to unravel the basic mechanisms involved in the relationship between the co-expression of PSMA2 and GLP-1R in T2D-linked cervical cancer, and their downregulation by Exendin-4. The db/db mouse model (which carry a genetic mutation in the leptin receptor and develop T2D because of hyperphagia-linked obesity), which was used for the in vivo validation study, may not accurately represent the patient cohort used in this study. This would require further validation using other, more relevant preclinical models of T2D [[10]Xu YXZ Mishra S. Obesity-linked cancers: current knowledge, challenges and limitations in mechanistic studies and rodent models.Cancers (Basel). 2018 Dec 18; 10: 523Crossref Scopus (11) Google Scholar]. Another potential avenue that needs further exploration includes the anti-inflammatory effect of Exendin-4 that has been reported in experimental studies. Thus, an investigation of the crosstalk between hyperglycaemia and inflammation may provide additional insights into the beneficial effects of Exendin-4 in T2D-linked cervical cancer. Thus, a major question that remain unanswered is how the mechanistic link between GPL-1R and PSMA2 in T2D-linked cervical cancer works, and the relative contribution of both T2D-related hyperglycaemia and inflammation therein. Other limitations that are also pointed by the authors include a selection bias, since only samples from Chinese women were included and other confounding factors were not adjusted, such as previous treatment or other risk factors. Despite these limitations and unanswered pertinent questions, this study by Mao et al sets the foundation for future clinical trials to determine the anti-cancer effects of Exendin-4 for T2D-linked cervical cancer (and potentially other T2D-linked cancer types) and for basic research to unravel the underlying mechanisms involved. NM and SM wrote and edited the commentary. SM did the literature search used for the commentary. The authors do not have conflict of interest. SM's laboratory research is supported by the Canadian Institutes of Health Research (CIHR) and the Natural Sciences and Engineering Research Council of Canada (NSERC). Increased co-expression of PSMA2 and GLP-1 receptor in cervical cancer models in type 2 diabetes attenuated by Exendin-4: A translational case-control studyPSMA2 and GLP-1R expression in T2D-related cervical cancer specimens was increased and positively correlated, suggesting hyperglycaemia might promote cancer growth by increasing PSMA2 expression which could be attenuated by Exendin-4. Full-Text PDF Open Access

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