Investigation of active peptides from natural products that induce ER-stress-mediated apoptosis in cancer as potential therapeutics for kidney cancer, common in some genetic diseases: An in silico approach

Abstract

Background: Endoplasmic reticulum (ER) stress initiates an unfolded protein response (UPR) to re-establish ER homeostasis as an adaptive pathway in cancer. However, persistent ER stress triggers the apoptotic pathway usually observed in kidney cancer (KC). The term KC actually refers to a number of distinct cancers. Kidney cancer is generally observed in a number of genetic diseases. Treatment options for KC have changed greatly over the years. The most commonly used tyrosine kinase inhibitors, TKI, show conflicting results regarding their beneficial effects on patients, as demonstrated in different KC patient cohort studies, indicating that the underlying molecular mechanisms involved in KC are more complex and likely need combined therapies able to modulate the activity of endoplasmic reticulum. Methods: The purpose of this research was to generate peptides from natural products in sillico that might be used as kidney cancer potential modulators. For this aim, several methods were used: Target prediction, protein hydrolysis, and protein-peptide molecular docking have all been used as techniques. Results: The network of critical KC genes is composed of C3AR1, CSNK2A2, ACE, DPP4, CAPN1, FPR2, HLA-A, and MMP2, together with predicted kinases such as RPS6KA5, MAPK14, CSNK2A1, PRKCD, CDK1, and HIPK2, in addition to transcription factors such as IRF8, TCF3, ERG, CREB1, EZH2, SPI1, IRF1, and SUZ12. The identified molecular targets of the isolated peptides are: HLA class I histocompatibility antigen A-3, lipoxin A4, dipeptidyl peptidase IV, angiotensinconverting enzyme, cyclooxygenase-2, C3a anaphylatoxin chemotactic receptor, melanocortin receptor 4, neurotensin receptor 1, mu opioid receptor, delta opioid receptor, and calpain 1. Conclusion: Overall, the results showed that GVSK, PGP, WQR, YGGF, and IF peptides are promising candidates for further study. Future work would be needed to test the therapeutic properties of these hydrolysate peptides using in vitro and in vivo approaches.