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For: Koehler JA, Kain T, Drucker DJ. Glucagon-like peptide-1 receptor activation inhibits growth and augments apoptosis in murine CT26 colon cancer cells. Endocrinology 2011;152:3362-72. [PMID: 21771884 DOI: 10.1210/en.2011-1201] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]

For:	Koehler JA, Kain T, Drucker DJ. Glucagon-like peptide-1 receptor activation inhibits growth and augments apoptosis in murine CT26 colon cancer cells. Endocrinology 2011;152:3362-72. [PMID: 21771884 DOI: 10.1210/en.2011-1201] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]

Number

Cited by Other Article(s)

Kelly CA, Sipos JA. Approach to the Patient With Thyroid Nodules: Considering GLP-1 Receptor Agonists. J Clin Endocrinol Metab 2025;110:e2080-e2087. [PMID: 39400117 DOI: 10.1210/clinem/dgae722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 08/28/2024] [Accepted: 10/11/2024] [Indexed: 10/15/2024]

Lin A, Ding Y, Li Z, Jiang A, Liu Z, Wong HZH, Cheng Q, Zhang J, Luo P. Glucagon-like peptide 1 receptor agonists and cancer risk: advancing precision medicine through mechanistic understanding and clinical evidence. Biomark Res 2025;13:50. [PMID: 40140925 PMCID: PMC11948983 DOI: 10.1186/s40364-025-00765-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Accepted: 03/13/2025] [Indexed: 03/28/2025] Open

Affiliation(s)

Anqi Lin Donghai County People's Hospital - Jiangnan University Smart Healthcare Joint Laboratory, Donghai County People's Hospital (Affiliated Kangda College of Nanjing Medical University), Lianyungang, Jiangsu Province, 222000, China Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China
Yanxi Ding Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China
Zhengrui Li Department of Oral and Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, Shanghai, China
Aimin Jiang Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
Zaoqu Liu Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
Hank Z H Wong Li Ka Shing, Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
Quan Cheng Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Hunan, China.
Jian Zhang Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China.
Peng Luo Donghai County People's Hospital - Jiangnan University Smart Healthcare Joint Laboratory, Donghai County People's Hospital (Affiliated Kangda College of Nanjing Medical University), Lianyungang, Jiangsu Province, 222000, China. Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China.

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Zhang Y, Xie Y, Xia S, Ge X, Li J, Liu F, Jia F, Wang S, Zhou Q, Gao M, Fang W, Zheng C. The Novel Dual GIP and GLP-1 Receptor Agonist Tirzepatide Attenuates Colon Cancer Development by Regulating Glucose Metabolism. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2411980. [PMID: 40125821 DOI: 10.1002/advs.202411980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 03/10/2025] [Indexed: 03/25/2025]

Wang C, Wu Z, Zhou J, Cheng B, Huang Y. Semaglutide, a glucagon-like peptide-1 receptor agonist, inhibits oral squamous cell carcinoma growth through P38 MAPK signaling pathway. J Cancer Res Clin Oncol 2025;151:103. [PMID: 40055197 PMCID: PMC11889073 DOI: 10.1007/s00432-025-06154-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Accepted: 02/26/2025] [Indexed: 03/12/2025]

Ungvari Z, Bartha Á, Ungvari A, Fekete M, Bianchini G, Győrffy B. Prognostic impact of glucagon-like peptide-1 receptor (GLP1R) expression on cancer survival and its implications for GLP-1R agonist therapy: an integrative analysis across multiple tumor types. GeroScience 2025:10.1007/s11357-024-01494-5. [PMID: 39777709 DOI: 10.1007/s11357-024-01494-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 12/17/2024] [Indexed: 01/11/2025] Open

Abstract

Glucagon-like peptide-1 receptor (GLP-1R) agonists, such as exenatide (Byetta, Bydureon), liraglutide (Victoza, Saxenda), albiglutide (Tanzeum), dulaglutide (Trulicity), lixisenatide (Lyxumia, Adlyxin), semaglutide (Ozempic, Rybelsus, Wegovy), and tirzepatide (Mounjaro, Zepbound), are widely used for the treatment of type 2 diabetes mellitus (T2DM) and obesity. While these agents are well known for their metabolic benefits, there is growing interest in their potential effects on cancer biology. However, the role of GLP-1R agonists in cancer remains complex and not fully understood, particularly across different tumor types. This study aimed to evaluate the prognostic significance of GLP1R expression on overall survival across various cancer types. Using a comprehensive analysis of gene expression data and survival outcomes a large cohorts of different tumor types, we employed Cox proportional hazards survival analyses, coupled with false discovery rate determinations, to explore correlations between GLP1R expression and survival. The integrated database included thousands of cancer specimens with available overall survival time and event data from numerous independent cohorts, providing a robust platform for survival analysis. Our findings reveal that increased GLP1R expression is associated with improved overall survival in cancers such as bladder cancer, breast cancer, esophageal adenocarcinoma, renal clear cell carcinoma, and thyroid carcinoma. Conversely, higher GLP1R expression is linked to poorer survival outcomes in cervical squamous cell carcinoma, lung squamous cell carcinoma, stomach adenocarcinoma, and uterine corpus endometrial carcinoma. Additionally, GLP1R expression showed no significant impact on overall survival in cancers such as esophageal squamous cell carcinoma, colon cancer, head-neck squamous cell carcinoma, renal papillary cell carcinoma, hepatocellular carcinoma, lung adenocarcinoma, ovarian cancer, and pancreatic cancer. In conclusion, GLP1R expression levels serve as an important biomarker with potential prognostic significance across multiple cancers, demonstrating both protective and adverse associations depending on the tumor type. These findings highlight the complex role of GLP-1R agonists in cancer risk and survival, suggesting that the therapeutic use of these agents should be carefully tailored to the individual patient's cancer risk profile.

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Li W, Lyu W, Liu S, Ruan F, Zhang X. GLP1R boosts survival, migration and invasion of endometrial cancer cells and protects against ferroptotic cell death. J OBSTET GYNAECOL 2024;44:2301324. [PMID: 38269495 DOI: 10.1080/01443615.2023.2301324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 12/29/2023] [Indexed: 01/26/2024]

Ibrahim SS, Ibrahim RS, Arabi B, Brockmueller A, Shakibaei M, Büsselberg D. The effect of GLP-1R agonists on the medical triad of obesity, diabetes, and cancer. Cancer Metastasis Rev 2024;43:1297-1314. [PMID: 38801466 PMCID: PMC11554930 DOI: 10.1007/s10555-024-10192-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2024] [Accepted: 05/21/2024] [Indexed: 05/29/2024]

Ji L, He X, Min X, Yang H, Wu W, Xu H, Chen J, Mei A. Glucagon-like peptide-1 receptor agonists in neoplastic diseases. Front Endocrinol (Lausanne) 2024;15:1465881. [PMID: 39371922 PMCID: PMC11449759 DOI: 10.3389/fendo.2024.1465881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Accepted: 08/28/2024] [Indexed: 10/08/2024] Open

Shieh C, Thompson HJ, McLaughlin E, Chiang CW, Hussan H. Advancements in Understanding and Preventing Obesity-Related Colon Cancer. Cancer J 2024;30:357-369. [PMID: 39312456 DOI: 10.1097/ppo.0000000000000744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/25/2024]

Sharma B, Twelker K, Nguyen C, Ellis S, Bhatia ND, Kuschner Z, Agriantonis A, Agriantonis G, Arnold M, Dave J, Mestre J, Shafaee Z, Arora S, Ghanta H, Whittington J. Bile Acids in Pancreatic Carcinogenesis. Metabolites 2024;14:348. [PMID: 39057671 PMCID: PMC11278541 DOI: 10.3390/metabo14070348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 06/10/2024] [Accepted: 06/19/2024] [Indexed: 07/28/2024] Open

Affiliation(s)

Bharti Sharma Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.) Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
Kate Twelker Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.) Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
Cecilia Nguyen Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.) Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
Scott Ellis Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.) Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
Navin D. Bhatia Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.) Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
Zachary Kuschner Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.) Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
Andrew Agriantonis Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
George Agriantonis Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.) Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
Monique Arnold Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
Jasmine Dave Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.) Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
Juan Mestre Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.) Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
Zahra Shafaee Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.) Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
Shalini Arora Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.) Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
Hima Ghanta Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.) Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
Jennifer Whittington Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.) Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)

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Tsuji S, Kudo U, Hatakeyama R, Shoda K, Nakamura S, Shimazawa M. Linagliptin decreased the tumor progression on glioblastoma model. Biochem Biophys Res Commun 2024;711:149897. [PMID: 38608433 DOI: 10.1016/j.bbrc.2024.149897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 04/04/2024] [Accepted: 04/04/2024] [Indexed: 04/14/2024]

Ligumsky H, Amir S, Arbel Rubinstein T, Guion K, Scherf T, Karasik A, Wolf I, Rubinek T. Glucagon-like peptide-1 analogs activate AMP kinase leading to reversal of the Warburg metabolic switch in breast cancer cells. Med Oncol 2024;41:138. [PMID: 38705935 DOI: 10.1007/s12032-024-02390-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 04/24/2024] [Indexed: 05/07/2024]

Laeeq T, Ahmed M, Sattar H, Zeeshan MH, Ali MB. Role of SGLT2 Inhibitors, DPP-4 Inhibitors, and Metformin in Pancreatic Cancer Prevention. Cancers (Basel) 2024;16:1325. [PMID: 38611003 PMCID: PMC11011099 DOI: 10.3390/cancers16071325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 03/08/2024] [Accepted: 03/27/2024] [Indexed: 04/14/2024] Open

Baran O, Akgun MY, Kayhan A, Evran S, Ozbek A, Akyoldas G, Samanci MY, Demirel N, Sonmez D, Serin H, Kocak A, Kemerdere R, Tanriverdi T. The association between calreticulin and glucagon-like peptide-1 expressions with prognostic factors in high-grade gliomas. J Cancer Res Ther 2024;20:25-32. [PMID: 38554294 DOI: 10.4103/jcrt.jcrt_1519_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 08/26/2022] [Indexed: 04/01/2024]

Wilbon SS, Kolonin MG. GLP1 Receptor Agonists-Effects beyond Obesity and Diabetes. Cells 2023;13:65. [PMID: 38201269 PMCID: PMC10778154 DOI: 10.3390/cells13010065] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 12/22/2023] [Accepted: 12/24/2023] [Indexed: 01/12/2024] Open

Ammann M, Santol J, Pereyra D, Kalchbrenner T, Wuerger T, Laengle J, Smoot RL, Hulla W, Laengle F, Starlinger P. Glucagon-like peptide-1 and glucagon-like peptide-2 regulation during human liver regeneration. Sci Rep 2023;13:15980. [PMID: 37749369 PMCID: PMC10519971 DOI: 10.1038/s41598-023-43283-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Accepted: 09/21/2023] [Indexed: 09/27/2023] Open

Cuttica CM, Briata IM, DeCensi A. Novel Treatments for Obesity: Implications for Cancer Prevention and Treatment. Nutrients 2023;15:3737. [PMID: 37686769 PMCID: PMC10490004 DOI: 10.3390/nu15173737] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 08/23/2023] [Accepted: 08/24/2023] [Indexed: 09/10/2023] Open

Yarmolinsky J, Bouras E, Constantinescu A, Burrows K, Bull CJ, Vincent EE, Martin RM, Dimopoulou O, Lewis SJ, Moreno V, Vujkovic M, Chang KM, Voight BF, Tsao PS, Gunter MJ, Hampe J, Pellatt AJ, Pharoah PDP, Schoen RE, Gallinger S, Jenkins MA, Pai RK, Gill D, Tsilidis KK. Genetically proxied glucose-lowering drug target perturbation and risk of cancer: a Mendelian randomisation analysis. Diabetologia 2023;66:1481-1500. [PMID: 37171501 PMCID: PMC10317892 DOI: 10.1007/s00125-023-05925-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 03/13/2023] [Indexed: 05/13/2023]

Abstract

AIMS/HYPOTHESIS

Epidemiological studies have generated conflicting findings on the relationship between glucose-lowering medication use and cancer risk. Naturally occurring variation in genes encoding glucose-lowering drug targets can be used to investigate the effect of their pharmacological perturbation on cancer risk.

METHODS

We developed genetic instruments for three glucose-lowering drug targets (peroxisome proliferator activated receptor γ [PPARG]; sulfonylurea receptor 1 [ATP binding cassette subfamily C member 8 (ABCC8)]; glucagon-like peptide 1 receptor [GLP1R]) using summary genetic association data from a genome-wide association study of type 2 diabetes in 148,726 cases and 965,732 controls in the Million Veteran Program. Genetic instruments were constructed using cis-acting genome-wide significant (p<5×10-8) SNPs permitted to be in weak linkage disequilibrium (r2<0.20). Summary genetic association estimates for these SNPs were obtained from genome-wide association study (GWAS) consortia for the following cancers: breast (122,977 cases, 105,974 controls); colorectal (58,221 cases, 67,694 controls); prostate (79,148 cases, 61,106 controls); and overall (i.e. site-combined) cancer (27,483 cases, 372,016 controls). Inverse-variance weighted random-effects models adjusting for linkage disequilibrium were employed to estimate causal associations between genetically proxied drug target perturbation and cancer risk. Co-localisation analysis was employed to examine robustness of findings to violations of Mendelian randomisation (MR) assumptions. A Bonferroni correction was employed as a heuristic to define associations from MR analyses as 'strong' and 'weak' evidence.

RESULTS

In MR analysis, genetically proxied PPARG perturbation was weakly associated with higher risk of prostate cancer (for PPARG perturbation equivalent to a 1 unit decrease in inverse rank normal transformed HbA1c: OR 1.75 [95% CI 1.07, 2.85], p=0.02). In histological subtype-stratified analyses, genetically proxied PPARG perturbation was weakly associated with lower risk of oestrogen receptor-positive breast cancer (OR 0.57 [95% CI 0.38, 0.85], p=6.45×10-3). In co-localisation analysis, however, there was little evidence of shared causal variants for type 2 diabetes liability and cancer endpoints in the PPARG locus, although these analyses were likely underpowered. There was little evidence to support associations between genetically proxied PPARG perturbation and colorectal or overall cancer risk or between genetically proxied ABCC8 or GLP1R perturbation with risk across cancer endpoints.

CONCLUSIONS/INTERPRETATION

Our drug target MR analyses did not find consistent evidence to support an association of genetically proxied PPARG, ABCC8 or GLP1R perturbation with breast, colorectal, prostate or overall cancer risk. Further evaluation of these drug targets using alternative molecular epidemiological approaches may help to further corroborate the findings presented in this analysis.

DATA AVAILABILITY

Summary genetic association data for select cancer endpoints were obtained from the public domain: breast cancer ( https://bcac.ccge.medschl.cam.ac.uk/bcacdata/ ); and overall prostate cancer ( http://practical.icr.ac.uk/blog/ ). Summary genetic association data for colorectal cancer can be accessed by contacting GECCO (kafdem at fredhutch.org). Summary genetic association data on advanced prostate cancer can be accessed by contacting PRACTICAL (practical at icr.ac.uk). Summary genetic association data on type 2 diabetes from Vujkovic et al (Nat Genet, 2020) can be accessed through dbGAP under accession number phs001672.v3.p1 (pha004945.1 refers to the European-specific summary statistics). UK Biobank data can be accessed by registering with UK Biobank and completing the registration form in the Access Management System (AMS) ( https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access ).

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Affiliation(s)

James Yarmolinsky MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK. Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
Emmanouil Bouras Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece
Andrei Constantinescu MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
Kimberley Burrows MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
Caroline J Bull MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK School of Translational Health Sciences, University of Bristol, Bristol, UK
Emma E Vincent MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK School of Translational Health Sciences, University of Bristol, Bristol, UK
Richard M Martin MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK NIHR Bristol Biomedical Research Centre, University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol, Bristol, UK
Olympia Dimopoulou MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
Sarah J Lewis MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
Victor Moreno Biomarkers and Susceptibility Unit, Oncology Data Analytics Program, Catalan Institute of Oncology (ICO), L'Hospitalet de Llobregat, Barcelona, Spain Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain
Marijana Vujkovic Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
Kyong-Mi Chang Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
Benjamin F Voight Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Institute of Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA, USA
Philip S Tsao VA Palo Alto Epidemiology Research and Information Center for Genomics, VA Palo Alto Health Care System, Palo Alto, CA, USA Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
Marc J Gunter Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France
Jochen Hampe Department of Medicine I, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany
Andrew J Pellatt University of Texas MD Anderson Cancer Center, Houston, TX, USA
Paul D P Pharoah Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
Robert E Schoen Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
Steven Gallinger Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada
Mark A Jenkins Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia
Rish K Pai Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, AZ, USA
Dipender Gill Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, London, UK
Kostas K Tsilidis Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, London, UK

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Ramírez-Perdomo A, Márquez-Barrios G, Gutiérrez-Castañeda LD, Parra-Medina R. NEUROENDOCRINE PEPTIDES IN THE PATHOGENESIS OF COLORECTAL CARCINOMA. Exp Oncol 2023;45:3-16. [PMID: 37417286 DOI: 10.15407/exp-oncology.2023.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Indexed: 07/08/2023]

McCauley HA, Riedman AM, Enriquez JR, Zhang X, Watanabe-Chailland M, Sanchez JG, Kechele DO, Paul EF, Riley K, Burger C, Lang RA, Wells JM. Enteroendocrine Cells Protect the Stem Cell Niche by Regulating Crypt Metabolism in Response to Nutrients. Cell Mol Gastroenterol Hepatol 2023;15:1293-1310. [PMID: 36608902 PMCID: PMC10140799 DOI: 10.1016/j.jcmgh.2022.12.016] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 12/27/2022] [Accepted: 12/27/2022] [Indexed: 01/09/2023]

Abstract

BACKGROUND & AIMS

The intestinal stem cell niche is exquisitely sensitive to changes in diet, with high-fat diet, caloric restriction, and fasting resulting in altered crypt metabolism and intestinal stem cell function. Unlike cells on the villus, cells in the crypt are not immediately exposed to the dynamically changing contents of the lumen. We hypothesized that enteroendocrine cells (EECs), which sense environmental cues and in response release hormones and metabolites, are essential for relaying the luminal and nutritional status of the animal to cells deep in the crypt.

METHODS

We used the tamoxifen-inducible VillinCreERT2 mouse model to deplete EECs (Neurog3fl/fl) from adult intestinal epithelium and we generated human intestinal organoids from wild-type and NEUROGENIN 3 (NEUROG3)-null human pluripotent stem cells. We used indirect calorimetry, 1H-Nuclear Magnetic Resonance (NMR) metabolomics, mitochondrial live imaging, and the Seahorse bioanalyzer (Agilent Technologies) to assess metabolism. Intestinal stem cell activity was measured by proliferation and enteroid-forming capacity. Transcriptional changes were assessed using 10x Genomics single-cell sequencing.

RESULTS

Loss of EECs resulted in increased energy expenditure in mice, an abundance of active mitochondria, and a shift of crypt metabolism to fatty acid oxidation. Crypts from mouse and human intestinal organoids lacking EECs displayed increased intestinal stem cell activity and failed to activate phosphorylation of downstream target S6 kinase ribosomal protein, a marker for activity of the master metabolic regulator mammalian target of rapamycin (mTOR). These phenotypes were similar to those observed when control mice were deprived of nutrients.

CONCLUSIONS

EECs are essential regulators of crypt metabolism. Depletion of EECs recapitulated a fasting metabolic phenotype despite normal levels of ingested nutrients. These data suggest that EECs are required to relay nutritional information to the stem cell niche and are essential regulators of intestinal metabolism.

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Affiliation(s)

Heather A McCauley Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Center for Stem Cell and Organoid Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina.
Anne Marie Riedman Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Center for Stem Cell and Organoid Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
Jacob R Enriquez Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Center for Stem Cell and Organoid Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
Xinghao Zhang Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Center for Stem Cell and Organoid Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
Miki Watanabe-Chailland Nuclear Magnetic Resonance-Based Metabolomics Core Facility, Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
J Guillermo Sanchez Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Center for Stem Cell and Organoid Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
Daniel O Kechele Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Center for Stem Cell and Organoid Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
Emily F Paul Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Center for Stem Cell and Organoid Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
Kayle Riley Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Center for Stem Cell and Organoid Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Postbaccalaureate Research Education Program, University of Cincinnati College of Medicine, Cincinnati, Ohio
Courtney Burger The Visual Systems Group, Abrahamson Pediatric Eye Institute, Division of Pediatric Ophthalmology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
Richard A Lang Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; The Visual Systems Group, Abrahamson Pediatric Eye Institute, Division of Pediatric Ophthalmology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
James M Wells Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Center for Stem Cell and Organoid Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio

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Samuel SM, Varghese E, Kubatka P, Büsselberg D. Tirzepatide-Friend or Foe in Diabetic Cancer Patients? Biomolecules 2022;12:1580. [PMID: 36358930 PMCID: PMC9687454 DOI: 10.3390/biom12111580] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 10/12/2022] [Accepted: 10/25/2022] [Indexed: 09/25/2023] Open

Tong G, Peng T, Chen Y, Sha L, Dai H, Xiang Y, Zou Z, He H, Wang S. Effects of GLP-1 Receptor Agonists on Biological Behavior of Colorectal Cancer Cells by Regulating PI3K/AKT/mTOR Signaling Pathway. Front Pharmacol 2022;13:901559. [PMID: 36034798 PMCID: PMC9399678 DOI: 10.3389/fphar.2022.901559] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 04/19/2022] [Indexed: 11/13/2022] Open

Sun H, Qi X. The role of insulin and incretin-based drugs in biliary tract cancer: epidemiological and experimental evidence. Discov Oncol 2022;13:70. [PMID: 35933633 PMCID: PMC9357599 DOI: 10.1007/s12672-022-00536-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Accepted: 07/26/2022] [Indexed: 11/29/2022] Open

Abdul-Maksoud RS, Elsayed WSH, Rashad NM, Elsayed RS, Elshorbagy S, Hamed MG. GLP-1R polymorphism (rs1042044) and expression are associated with the risk of papillary thyroid cancer among the Egyptian population. Gene X 2022;834:146597. [PMID: 35598685 DOI: 10.1016/j.gene.2022.146597] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/26/2022] [Accepted: 05/16/2022] [Indexed: 12/28/2022] Open

Zhu S, Bai Q, Li L, Xu T. Drug repositioning in drug discovery of T2DM and repositioning potential of antidiabetic agents. Comput Struct Biotechnol J 2022;20:2839-2847. [PMID: 35765655 PMCID: PMC9189996 DOI: 10.1016/j.csbj.2022.05.057] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 05/30/2022] [Accepted: 05/30/2022] [Indexed: 12/19/2022] Open

The Regulatory Role of Neuropeptide Gene Glucagon in Colorectal Cancer: A Comprehensive Bioinformatic Analysis. DISEASE MARKERS 2022;2022:4262600. [PMID: 35340411 PMCID: PMC8956438 DOI: 10.1155/2022/4262600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 01/05/2022] [Accepted: 01/08/2022] [Indexed: 11/26/2022]

Abstract

Background

Colorectal cancer is highly prevalent and causes high global mortality, and glucagon axis has been implicated in colon cancer. The present study is aimed at investigating the regulating mechanisms of glucagon involvement in colorectal cancer.

Methods

Publicly available data from the TCGA database was utilized to explore the expression pattern and regulating role of glucagon (GCG) in colorectal cancer (COADREAD) including colon adenocarcinomas (COAD) and rectum adenocarcinomas (READ). Statistical analyses were performed using the R software packages and public web servers. The expression pattern and prognostic significance of GCG gene in pan-cancer and TCGA-COADREAD data were investigated by performing unpaired and paired sample analyses. The association of GCG expression with clinical characteristics was investigated using logistic regression analysis. Univariate cox regression analysis was performed to test the prognostic value of GCG expression for overall survival in COADREAD patients. GCG-significantly correlated genes were obtained. Biological functions and signaling pathways were identified by performing functional enrichment analysis and Gene Set Enrichment Analysis (GSEA). Additionally, the potential involvement of GCG in tumor immunity was researched by investigating the correlation between GCG expression and 24 tumor infiltrating immune cells.

Results

GCG was found to be significantly downregulated in COADREAD tumor samples compared with healthy control samples. GCG gene was shown to be associated with the prognostic outcomes of COADREAD, whereby its upregulation predicted improved survival outcomes. Functional enrichment analysis showed that the top 100 positively and top 100 negatively GCG-correlated genes were mainly enriched in three signaling pathways including ribosome, nitrogen metabolism, and proximal tubule bicarbonate reclamation. The GSEA showed that GCG-significantly correlated genes were mainly enriched in cell cycle-related pathways (reactome cell cycle, reactome cell cycle mitotic, reactome cell cycle checkpoints, reactome M phase, Reactome G2 M DNA damage checkpoint, and Reactome G2 M checkpoints), neuropeptide ligand receptor interaction, RHO GTPases signaling, WNT signaling, RUNX1 signaling, NOTCH signaling, ESR signaling, HCMV infection, and oxidative stress-related signaling. GCG was positively correlated with Th17 cells, pDC, macrophages, TFH cells, iDC, Tem, B cells, dendritic cells, neutrophils, mast cells, and eosinophils and was negatively associated with NK cells.

Conclusions

GCG dysregulation with high prognostic value in COADREAD was noted. Several tumor progression-related pathways and tumor immune-modulatory cells were linked to GCG expression in COADREAD. Therefore, GCG may be regarded as a potential therapeutic target for treating colorectal cancer.

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Wang J, Kim CH. Differential Risk of Cancer Associated with Glucagon-like Peptide-1 Receptor Agonists: Analysis of Real-world Databases. Endocr Res 2022;47:18-25. [PMID: 34459679 DOI: 10.1080/07435800.2021.1955255] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]

Vekic J, Zeljkovic A, Stefanovic A, Giglio RV, Ciaccio M, Rizzo M. Diabetes and Colorectal Cancer Risk: A New Look at Molecular Mechanisms and Potential Role of Novel Antidiabetic Agents. Int J Mol Sci 2021;22:12409. [PMID: 34830295 PMCID: PMC8622770 DOI: 10.3390/ijms222212409] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 11/14/2021] [Accepted: 11/15/2021] [Indexed: 12/13/2022] Open

Batty MJ, Chabrier G, Sheridan A, Gage MC. Metabolic Hormones Modulate Macrophage Inflammatory Responses. Cancers (Basel) 2021;13:cancers13184661. [PMID: 34572888 PMCID: PMC8467249 DOI: 10.3390/cancers13184661] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 08/31/2021] [Accepted: 09/13/2021] [Indexed: 12/17/2022] Open

Jaiswal P, Tripathi V, Nayak A, Kataria S, Lukashevich V, Das A, Parmar HS. A molecular link between diabetes and breast cancer: Therapeutic potential of repurposing incretin-based therapies for breast cancer. Curr Cancer Drug Targets 2021;21:829-848. [PMID: 34468298 DOI: 10.2174/1568009621666210901101851] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 07/15/2021] [Accepted: 07/20/2021] [Indexed: 11/22/2022]

Yan M, Shen M, Xu L, Huang J, He G, An M, Li X, Gao Z, Meng X. Inactivation of Pancreatic Stellate Cells by Exendin-4 Inhibits the Migration and Invasion of Pancreatic Cancer Cells. Onco Targets Ther 2020;13:9455-9463. [PMID: 33061431 PMCID: PMC7522302 DOI: 10.2147/ott.s259853] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 08/16/2020] [Indexed: 12/17/2022] Open

Kojima M, Takahashi H, Kuwashiro T, Tanaka K, Mori H, Ozaki I, Kitajima Y, Matsuda Y, Ashida K, Eguchi Y, Anzai K. Glucagon-Like Peptide-1 Receptor Agonist Prevented the Progression of Hepatocellular Carcinoma in a Mouse Model of Nonalcoholic Steatohepatitis. Int J Mol Sci 2020;21:ijms21165722. [PMID: 32785012 PMCID: PMC7460814 DOI: 10.3390/ijms21165722] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 08/05/2020] [Accepted: 08/06/2020] [Indexed: 12/16/2022] Open

Affiliation(s)

Motoyasu Kojima Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (M.K.); (H.T.); (T.K.); (K.T.); (H.M.); (I.O.); (Y.K.); (Y.M.); (K.A.); (Y.E.)
Hirokazu Takahashi Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (M.K.); (H.T.); (T.K.); (K.T.); (H.M.); (I.O.); (Y.K.); (Y.M.); (K.A.); (Y.E.) Liver Center, Saga University Hospital, Faculty of Medicine, Saga University, Saga 849-8501, Japan
Takuya Kuwashiro Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (M.K.); (H.T.); (T.K.); (K.T.); (H.M.); (I.O.); (Y.K.); (Y.M.); (K.A.); (Y.E.)
Kenichi Tanaka Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (M.K.); (H.T.); (T.K.); (K.T.); (H.M.); (I.O.); (Y.K.); (Y.M.); (K.A.); (Y.E.)
Hitoe Mori Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (M.K.); (H.T.); (T.K.); (K.T.); (H.M.); (I.O.); (Y.K.); (Y.M.); (K.A.); (Y.E.)
Iwata Ozaki Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (M.K.); (H.T.); (T.K.); (K.T.); (H.M.); (I.O.); (Y.K.); (Y.M.); (K.A.); (Y.E.)
Yoichiro Kitajima Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (M.K.); (H.T.); (T.K.); (K.T.); (H.M.); (I.O.); (Y.K.); (Y.M.); (K.A.); (Y.E.) Department of Radiology, Eguchi Hospital, Ogi 845-0032, Japan
Yayoi Matsuda Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (M.K.); (H.T.); (T.K.); (K.T.); (H.M.); (I.O.); (Y.K.); (Y.M.); (K.A.); (Y.E.) Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
Kenji Ashida Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (M.K.); (H.T.); (T.K.); (K.T.); (H.M.); (I.O.); (Y.K.); (Y.M.); (K.A.); (Y.E.) Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
Yuichiro Eguchi Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (M.K.); (H.T.); (T.K.); (K.T.); (H.M.); (I.O.); (Y.K.); (Y.M.); (K.A.); (Y.E.) Liver Center, Saga University Hospital, Faculty of Medicine, Saga University, Saga 849-8501, Japan
Keizo Anzai Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (M.K.); (H.T.); (T.K.); (K.T.); (H.M.); (I.O.); (Y.K.); (Y.M.); (K.A.); (Y.E.) Correspondence: ; Tel./Fax: +81-952-34-2362

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Pleiotropic effects of anti-diabetic drugs: A comprehensive review. Eur J Pharmacol 2020;884:173349. [PMID: 32650008 DOI: 10.1016/j.ejphar.2020.173349] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Revised: 06/24/2020] [Accepted: 07/03/2020] [Indexed: 12/18/2022]

Eftekhari S, Montazeri H, Tarighi P. Synergistic anti-tumor effects of Liraglutide, a glucagon-like peptide-1 receptor agonist, along with Docetaxel on LNCaP prostate cancer cell line. Eur J Pharmacol 2020;878:173102. [DOI: 10.1016/j.ejphar.2020.173102] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 03/27/2020] [Accepted: 04/06/2020] [Indexed: 12/29/2022]

The Neuropeptide System and Colorectal Cancer Liver Metastases: Mechanisms and Management. Int J Mol Sci 2020;21:ijms21103494. [PMID: 32429087 PMCID: PMC7279011 DOI: 10.3390/ijms21103494] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 05/05/2020] [Accepted: 05/11/2020] [Indexed: 12/24/2022] Open

Abstract

Colorectal cancer (CRC), classified as the third most prevalent cancer worldwide, remains to be a clinical and research challenge. It is estimated that ~50% of CRC patients die from distant metastases, with treatment of this complication still posing significant difficulties. While liver metastasis (LM) cascade is known in the literature, its mechanisms are still unclear and remain studied in different research models. A connection is suggested between nervous system dysfunctions and a range of Neurotransmitters (Nts) (including Neuropeptides, NPs), Neurotrophins (Ntt) and their receptors (Rs) in CRC liver metastasis development. Studies on the role of NP/NP-Rs in the progression and metastasis of CRC, show the complexity of brain–tumor interactions, caused by their different forms of release to the extracellular environment (endocrine, autocrine, paracrine and neurocrine). Many stages of LM are connected to the activity of pro-inflammatory, e.g., Corticotropin-releasing Hormone Receptor 1 (CRHR1), Neuropeptide Y (NPY) and Neurotensin (NT), anti-inflammatory, e.g., Calcitonin Gene-related Peptide (CGRP), CRHR2 and Vasoactive Intestinal Polypeptide (VIP) or dual role neuropeptides, e.g., Substance P (SP). The regulation of the local immunological profile (e.g., CRH/CRHRs), dysfunctions of enteroprotective role of NPs on epithelial cells (e.g., NT/NT-R), as well as structural-functional changes in enteric nervous system innervation of the tumor are also important. More research is needed to understand the exact mechanisms of communication between the neurons and tumor cells. The knowledge on the mechanisms regulating tumor growth and different stages of metastasis, as well as effects of the action of a numerous group of Nts/NPs/Ntt as growth factors, have implications for future therapeutic strategies. To obtain the best treatment outcomes, it is important to use signaling pathways common for many NPs, as well to develop a range of broad-spectrum antagonists. This review aims to summarize the current knowledge on the importance of neuroactive molecules in the promotion of the invasion-metastasis cascade in CRC, as well as the improvements of clinical management of CRC liver metastasis.

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Wenjing H, Shao Y, Yu Y, Huang W, Feng G, Li J. Exendin-4 enhances the sensitivity of prostate cancer to enzalutamide by targeting Akt activation. Prostate 2020;80:367-375. [PMID: 31967357 DOI: 10.1002/pros.23951] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Accepted: 12/30/2019] [Indexed: 12/23/2022]

Zhang D, Ma M, Liu Y. Protective Effects of Incretin Against Age-Related Diseases. Curr Drug Deliv 2019;16:793-806. [PMID: 31622202 DOI: 10.2174/1567201816666191010145029] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 07/01/2019] [Accepted: 09/19/2019] [Indexed: 12/11/2022]

Chai S, Yu S, Yang Z, Wu S, Gao L, Wang H, Zhang Y, Zhan S, Ji L, Sun F. Effect of incretin-based therapies on cancers of digestive system among 101 595 patients with type 2 diabetes mellitus: a systematic review and network meta-analysis combining 84 trials with a median duration of 30 weeks. BMJ Open Diabetes Res Care 2019;7:e000728. [PMID: 31641525 PMCID: PMC6777405 DOI: 10.1136/bmjdrc-2019-000728] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Revised: 08/24/2019] [Accepted: 09/02/2019] [Indexed: 02/06/2023] Open

Abstract

OBJECTIVES

To evaluate the risk of cancers of digestive system with incretin-based therapies among patients with type 2 diabetes mellitus.

RESEARCH DESIGN AND METHODS

Medline, Embase, Cochrane Library and ClinicalTrials.gov databases were searched for randomized controlled clinical trials that compared incretin-based drugs with placebo or other antidiabetic drugs. Paired reviewers independently screened citations, extracted data and assessed risk of bias of included studies. Network meta-analysis was performed, followed by subgroup analysis. The Grading of Recommendations Assessment, Development and Evaluation system was used to assess the quality of evidence.

RESULTS

A total of 84 studies (n=101 595) involving cancers of digestive system were identified (a median follow-up of 30 weeks). The risk of cancers of digestive system with incretin-based therapies was comparable with insulin (OR: 0.86, 95% CI 0.27 to 2.69), metformin (OR: 0.32, 95% CI 0.07 to 1.38), sodium-glucose co-transporter 2 (OR: 5.26, 95% CI 0.58 to 47.41), sulfonylureas (OR: 1.27, 95% CI 0.68 to 2.39), thiazolidinediones (OR: 0.42, 95% CI 0.13 to 1.42), alpha-glucosidase inhibitors (OR: 2.98, 95% CI 0.12 to 73.80), and placebo (OR: 0.87, 95% CI 0.71 to 1.05). The results of subgroup analysis based on the type of digestive system cancers indicated that incretin-based therapies did not increase the risk of gastrointestinal cancers, respectively. The results of subgroup analysis based on age, duration, mean HbA1c, trial duration, and sample size did not indicate the risk of digestive system cancers.

CONCLUSIONS

Moderate to high Grading of Recommendations Assessment, Development and Evaluation evidence suggests that incretin-based therapies were not associated with an increased risk of cancer of digestive system in patients with type 2 diabetes mellitus.

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Bian Q, Chen J, Qiu W, Peng C, Song M, Sun X, Liu Y, Ding F, Chen J, Zhang L. Four targeted genes for predicting the prognosis of colorectal cancer: A bioinformatics analysis case. Oncol Lett 2019;18:5043-5054. [PMID: 31612015 PMCID: PMC6781647 DOI: 10.3892/ol.2019.10866] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 08/13/2019] [Indexed: 12/12/2022] Open

Yaribeygi H, Lhaf F, Sathyapalan T, Sahebkar A. Effects of novel antidiabetes agents on apoptotic processes in diabetes and malignancy: Implications for lowering tissue damage. Life Sci 2019;231:116538. [PMID: 31176776 DOI: 10.1016/j.lfs.2019.06.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 06/03/2019] [Accepted: 06/05/2019] [Indexed: 12/25/2022]

Sood A, Swislocki A. Nonglycemic Effects of GLP-1 Agonists: From a Starling to Lizards to People. Metab Syndr Relat Disord 2019;17:303-313. [PMID: 31145029 DOI: 10.1089/met.2018.0134] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open

Incretin-based Drugs and the Incidence of Colorectal Cancer in Patients with Type 2 Diabetes. Epidemiology 2019;29:246-253. [PMID: 29283894 DOI: 10.1097/ede.0000000000000793] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]

He W, Li J. Exendin-4 enhances radiation response of prostate cancer. Prostate 2018;78:1125-1133. [PMID: 30009503 DOI: 10.1002/pros.23687] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 06/22/2018] [Indexed: 12/27/2022]

Lu R, Yang J, Wei R, Ke J, Tian Q, Yu F, Liu J, Zhang J, Hong T. Synergistic anti-tumor effects of liraglutide with metformin on pancreatic cancer cells. PLoS One 2018;13:e0198938. [PMID: 29897998 PMCID: PMC5999272 DOI: 10.1371/journal.pone.0198938] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Accepted: 05/29/2018] [Indexed: 12/13/2022] Open

Ayoub BM, Mowaka S, Safar MM, Ashoush N, Arafa MG, Michel HE, Tadros MM, Elmazar MM, Mousa SA. Repositioning of Omarigliptin as a once-weekly intranasal Anti-parkinsonian Agent. Sci Rep 2018;8:8959. [PMID: 29895906 PMCID: PMC5997767 DOI: 10.1038/s41598-018-27395-0] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Accepted: 05/30/2018] [Indexed: 12/13/2022] Open

Affiliation(s)

Bassam M Ayoub Pharmaceutical Chemistry Department, Faculty of Pharmacy, The British University in Egypt, El-Sherouk city, Cairo, Egypt. The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, El-Sherouk city, Cairo, Egypt.
Shereen Mowaka Pharmaceutical Chemistry Department, Faculty of Pharmacy, The British University in Egypt, El-Sherouk city, Cairo, Egypt The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, El-Sherouk city, Cairo, Egypt Analytical Chemistry Department, Faculty of Pharmacy, Helwan University, Ein Helwan, Cairo, Egypt
Marwa M Safar The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, El-Sherouk city, Cairo, Egypt Pharmacology & Biochemistry Department, Faculty of Pharmacy, The British University in Egypt, El-Sherouk city, Cairo, Egypt Pharmacology & Toxicology Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini st., Cairo, Egypt
Nermeen Ashoush The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, El-Sherouk city, Cairo, Egypt Clinical Pharmacy and Pharmacy Practice Department, Faculty of Pharmacy, The British University in Egypt, El-Sherouk city, Cairo, Egypt
Mona G Arafa The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, El-Sherouk city, Cairo, Egypt Pharmaceutics Department, Faculty of Pharmacy, The British University in Egypt, El-Sherouk city, Cairo, Egypt Chemotheraputic Unit, Mansoura University Hospitals, Mansoura, 35516, Egypt
Haidy E Michel Pharmacology & Toxicology Department, Faculty of Pharmacy, Ain Shams University, El-Abaseya, Cairo, Egypt
Mariam M Tadros Analytical Chemistry Department, Faculty of Pharmacy, Ain Shams University, El-Abaseya, Cairo, Egypt
Mohamed M Elmazar The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, El-Sherouk city, Cairo, Egypt Pharmacology & Biochemistry Department, Faculty of Pharmacy, The British University in Egypt, El-Sherouk city, Cairo, Egypt
Shaker A Mousa The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, United States

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Mulvihill EE. Regulation of intestinal lipid and lipoprotein metabolism by the proglucagon-derived peptides glucagon like peptide 1 and glucagon like peptide 2. Curr Opin Lipidol 2018;29:95-103. [PMID: 29432213 PMCID: PMC5882252 DOI: 10.1097/mol.0000000000000495] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]

Wang H, Liu Y, Tian Q, Yang J, Lu R, Zhan S, Haukka J, Hong T. Incretin-based therapies and risk of pancreatic cancer in patients with type 2 diabetes: A meta-analysis of randomized controlled trials. Diabetes Obes Metab 2018;20:910-920. [PMID: 29193572 DOI: 10.1111/dom.13177] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Revised: 11/07/2017] [Accepted: 11/25/2017] [Indexed: 01/04/2023]

Stone TW, McPherson M, Gail Darlington L. Obesity and Cancer: Existing and New Hypotheses for a Causal Connection. EBioMedicine 2018;30:14-28. [PMID: 29526577 PMCID: PMC5952217 DOI: 10.1016/j.ebiom.2018.02.022] [Citation(s) in RCA: 161] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Revised: 02/12/2018] [Accepted: 02/23/2018] [Indexed: 02/07/2023] Open

Iwaya C, Nomiyama T, Komatsu S, Kawanami T, Tsutsumi Y, Hamaguchi Y, Horikawa T, Yoshinaga Y, Yamashita S, Tanaka T, Terawaki Y, Tanabe M, Nabeshima K, Iwasaki A, Yanase T. Exendin-4, a Glucagonlike Peptide-1 Receptor Agonist, Attenuates Breast Cancer Growth by Inhibiting NF-κB Activation. Endocrinology 2017;158:4218-4232. [PMID: 29045658 DOI: 10.1210/en.2017-00461] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2017] [Accepted: 10/09/2017] [Indexed: 02/06/2023]

Kosowska A, Gallego-Colon E, Garczorz W, Kłych-Ratuszny A, Aghdam MRF, Woz Niak M, Witek A, Wróblewska-Czech A, Cygal A, Wojnar J, Francuz T. Exenatide modulates tumor-endothelial cell interactions in human ovarian cancer cells. Endocr Connect 2017;6:856-865. [PMID: 29042458 PMCID: PMC5682419 DOI: 10.1530/ec-17-0294] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Accepted: 10/17/2017] [Indexed: 12/14/2022]