Glucagon-like peptide-1 (GLP-1) receptor agonists, known for their efficacy in treating diabetes by enhancing insulin secretion, are currently being investigated for their potential impact on prostate cancer (PCa). The intriguing possibility that these agents may influence cancer progression has led researchers to explore their effects beyond diabetes treatment. This fascinating development comes from a study led by Dr. Mohammed Shahait from the University of Sharjah and his team, published in the journal Cancers.
GLP-1, an incretin hormone, is synthesized in the brain stem, pancreas, and intestines and plays a crucial role in regulating postprandial blood sugar. To counteract its short half-life, GLP-1 receptor agonists (GLP-1RAs) have been developed and have been shown to be effective in treating diabetes. However, concerns have been raised about its possible link to cancers, such as thyroid cancer. Evidence on its association with prostate cancer remains inconclusive, prompting the authors to delve deeper into the mechanisms through which GLP-1RAs may influence prostate cancer cells.
The team explored several pathways, including the PI3K/Akt pathway, which affects the transcription factors pancreatic duodenal homeobox 1 (PDX1) and Forkhead box O1 (FoxO1), which are essential for cell proliferation. GLP-1 inhibits FoxO1, which promotes β-cell proliferation, and enhances PDX1 activity, thereby stimulating cell proliferation. In particular, GLP-1-RAs have shown potential to inhibit the proliferation of several cancer cells, including breast, ovarian, pancreatic, and prostate cancers.
In prostate cancer cells, activation of the GLP-1 receptor triggers the cAMP cascade, which inhibits extracellular signal-regulated kinases (ERKs) and cyclin D1, essential for DNA replication and cell cycle progression. By activating phosphokinase A and AMPK, GLP-1 counteracts mTOR, a key regulator of cellular activities, and increases levels of P27, an antiproliferative protein. This intricate network provides insight into the potential therapeutic impact of the GLP-1 receptor in prostate cancer.
Dr Shahait commented: “Our findings suggest that GLP-1-RAs, particularly when combined with treatments such as metformin or radiotherapy, exhibit a synergistic effect that significantly reduces tumour size. This opens up new avenues for the treatment of prostate cancer, especially for patients with metabolic syndrome.”
The researchers highlighted that inflammation, a significant factor in cancer progression, is mitigated by GLP-1-RAs through their anti-inflammatory properties. By reducing cytokine release and macrophage infiltration, GLP-1-RAs inhibit chronic inflammatory processes implicated in insulin resistance and cancer development.
In addition, the study investigated the role of metabolic syndrome in prostate cancer. Metabolic syndrome, characterized by insulin resistance and hyperinsulinemia, has been linked to increased incidence of prostate cancer and poorer patient outcomes. GLP-1-RAs, known for their anti-diabetic effects, may reduce this risk by improving metabolic health and inhibiting cancer cell proliferation.
In vitro studies demonstrated that GLP-1-RAs such as Ex-4 significantly reduced prostate cancer cell volume and enhanced the efficacy of radiotherapy and the chemotherapy drug docetaxel. The combination of Ex-4 and radiotherapy showed a remarkable reduction in tumor size, attributed to its dual effect on cell cycle arrest and apoptosis.
However, the clinical implications of these findings remain under investigation. While GLP-1-RAs have shown promise in preclinical studies, comprehensive clinical trials are needed to determine their efficacy and safety in patients with prostate cancer. Future research should focus on specific trials to evaluate the role of GLP-1-RAs in the treatment of prostate cancer, including their potential as a prophylactic treatment and adjunctive therapy in various stages of prostate cancer.
This study highlights the importance of exploring new therapeutic avenues for prostate cancer, particularly for patients with metabolic syndrome and diabetes. As Dr. Shahait and colleagues concluded, “Understanding the intricate relationship between GLP-1-RAs and prostate cancer could lead to innovative treatments that improve patient outcomes and quality of life.”
Journal reference
Alhajahjeh, A., Al-Faouri, R., Bahmad, H. F., Bader, T., Dobbs, R. W., Abdulelah, A. A., Abou-Kheir, W., Davicioni, E., Lee, D. I., & Shahait, M. (2024). From diabetes to oncology: the dual role of glucagon-like peptide-1 (GLP-1) receptor agonist in prostate cancer. Cancers, 16*(1538). DOI: https://doi.org/10.3390/cancers16081538
About the Author
Dr. Mohammed Shahait Dr. Shahait is a urologist renowned for his expertise and pioneering techniques in the Middle East. A graduate of the Jordan University of Science and Technology, his relentless pursuit of excellence led him to advanced training at prestigious institutions. He completed his residency at the American University of Beirut Medical Center, followed by specialized fellowships in Endourology at the University of Pittsburgh Medical Center and Robotic Urology at the University of Pennsylvania. Dr. Shahait has been instrumental in introducing innovative medical procedures to Jordan, including the first percutaneous renal cryotherapy and robotic radical prostatectomy. He currently serves patients with his unparalleled expertise in Dubai.
In addition to his clinical accolades, Dr. Shahait’s keen interest in advancing the field has been corroborated by important studies. He has received significant grants for his pioneering research, particularly on surgical margins after radical prostatectomy and the genomic landscape of bladder cancer in the Jordanian population. Dr. Shahait’s academic prowess is further reflected in his editorial roles in several prestigious urological journals.
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