Cardiovascular diseases (CVDs) and complications are often seen in patients with prostate cancer (PCa) and affect their clinical management. Despite acceptable safety profiles and patient compliance, androgen deprivation therapy (ADT), the mainstay of PCa treatment and chemotherapy, has increased cardiovascular risks and metabolic syndromes in patients. A growing body of evidence also suggests that patients with pre-existing cardiovascular conditions show an increased incidence of PCa and present with fatal forms of the disease. Therefore, it is possible that a molecular link exists between the two diseases, which has not yet been unraveled. This article provides insight into the connection between PCa and CVDs. In this context, we present our findings linking PCa progression with patients’ cardiovascular health by performing a comprehensive gene expression study, gene set enrichment (GSEA) and biological pathway analysis using publicly available data extracted from patients with advanced metastatic PCa. We also discuss the common androgen deprivation strategies and CVDs most frequently reported in PCa patients and present evidence from various clinical trials that suggest that therapy induces CVD in PCa patients.
Introduction: Colorectal cancer (CRC) is a leading cause of cancer related deaths worldwide. The balance between cancer cell proliferation and apoptosis, which maintains intestinal epithelial cell homeostasis, is disturbed in CRC. Furthermore, deregulation of the apoptotic pathway contributes to therapeutic resistance. Therefore, determination of the mechanisms employed by CRC cells to evade apoptosis is important for development of new therapeutic strategies. Our group has recently reported that neuropeptide Y (NPY), which is a 36-amino acid neuropeptide, is associated with increased angiogenic response in colon cancer. However, the regulatory role of NPY in cellular homeostasis in CRC is largely unknown. NPY is secreted by colon cancer cells that express Y1 receptors (Y1R). The aim of the present study was to investigate the role of NPY in regulation of cell growth and survival in CRC and to determine the apoptosis inducing effects of Y1R antagonist, BIBO 3304 trifluoroacetate (BIBO), in CT26 colon carcinoma cells. Methods: Correlation between NPY expression and cell cycle and apoptosis-related genes were analyzed in cBioPortal for cancer genomics with a sample number of 594 CRC patients from the cancer genome atlas database (TCGA). Based on the TCGA database, 16 apoptosis-related genes (11 proapoptotic and 5 antiapoptotic) were checked. The effect of Y1R blocker (BIBO, Bio-Techne, MN) on CT26 (ATCC) cell proliferation, apoptosis and cell cycle progression was determined by performing in vitro cell proliferation assay and flow cytometry. Results and Conclusion: NPY expression in CRC shows a positive correlation with pro-survival/anti-apoptotic genes (BCL2, BCL2L1, BCL2L2, BCL2A1, MCL1) and negative correlation with key genes associated with the induction of cellular apoptosis (GZMB, TRIB3, TPX2, BAX, BAK1, BAD, BID, BIK, BOK, HRK) in CRC. Decreased cell proliferation and increased apoptosis was observed in CT26 mouse CRC cells upon inhibition of Y1R. An increased number of CT26 cells in early and mid-apoptotic phase was observed upon treatment with Y1R antagonist, BIBO, compared to untreated cells. In addition, cell cycle analysis indicated an increase in cell numbers in the G1/S cell cycle transition phase in the BIBO treated group. Our findings therefore indicate that treatment of CT26 CRC cells with Y1R blocker results in cell cycle arrest, which provides an opportunity for the cells to either undergo repair mechanisms or follow the apoptotic pathway. Blocking the actions of NPY by Y1R blockers thus may be a promising therapeutic approach in CRC patients. Citation Format: Sooraj Kakkat, Steven McClellan, Debanjan Chakroborty, Chandrani Sarkar. Selective blockade of neuropeptide Y receptor 1 induces cell cycle arrest and promotes apoptosis in colon cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1424.
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