Cisplatin's potential for type 2 diabetes repositioning by inhibiting CDKN1A, FAS, and SESN1.
Cisplatin is a DNA-damaging chemotherapeutic agent used for treating cancer. Based on cDNA dataset analysis, we investigated how cisplatin modified gene expression and observed cisplatin-induced dysregulation and system-level variations relating to insulin resistance and type 2 diabetes mellitus (T2DM). T2DM is a multifactorial disease affecting 462 million people in the world, and drug-induced T2DM is a serious issue. To understand this etiology, we designed an integrative, system-level study to identify associations between cisplatin-induced differentially expressed genes (DEGs) and T2DM. From a list of differential expressed genes, cisplatin downregulated the cyclin-dependent kinase inhibitor 1 (CDKN1A), tumor necrosis factor (FAS), and sestrin-1 (SESN1) genes responsible for modifying signaling pathways, including the p53, JAK-STAT, FOXO, MAPK, mTOR, P13-AKT, Toll-like receptor (TLR), adipocytokine, and insulin signaling pathways. These enriched pathways were expressively associated with the disease. We observed significant gene signatures, including SMAD3, IRS, PDK1, PRKAA1, AKT, SOS, RAS, GRB2, MEK1/2, and ERK, interacting with source genes. This study revealed the value of system genetics for identifying the cisplatin-induced genetic variants responsible for the progression of T2DM. Also, by cross-validating gene expression data for T2DM islets, we found that downregulating IRS and PRK families is critical in insulin and T2DM signaling pathways. Cisplatin, by inhibiting CDKN1A, FAS, and SESN1, promotes IRS and PRK activity in a similar way to rosiglitazone (a popular drug used for T2DM treatment). Our integrative, network-based approach can help in understanding the drug-induced pathophysiological mechanisms of diabetes.
['Muhammad|Syed Aun|SA|', 'Qousain Naqvi|Syeda Tahira|ST|', 'Nguyen|Thanh|T|', 'Wu|Xiaogang|X|', 'Munir|Fahad|F|', 'Jamshed|Muhammad Babar|MB|', 'Zhang|QiYu|Q|']
D000970:Antineoplastic Agents D002945:Cisplatin D050759:Cyclin-Dependent Kinase Inhibitor p21 D003924:Diabetes Mellitus, Type 2 D006360:Heat-Shock Proteins D006801:Humans D007328:Insulin D015398:Signal Transduction
cDNA dataset T2DM Rosiglitazone Cisplatin-induced DEGs Systems biology