Tirzepatide alters oncogenic signaling pathways in colorectal cancer cells in vitro

Obesity prevalence is rapidly increasing worldwide, necessitating diverse treatment approaches ranging from pharmacotherapy to surgical interventions. Tirzepatide, a recently approved dual GIP/GLP-1 receptor agonist, has shown therapeutic promise, but its impact on cancer-related pathways remains unclear. This in vitro study investigated the molecular effects of tirzepatide on colorectal cancer SW48 cells by assessing the expression of key regulatory genes, including NF-kB, p53, c-Myc, and CASP8, after treatment with varying tirzepatide concentrations compared to untreated controls. Results demonstrated significant upregulation of the tumor suppressor gene p53 and the pro-apoptotic gene CASP8 (notably a 68.37-fold increase in one treatment group, P = 0.0002), alongside increased c-Myc expression in higher dose groups. These findings suggest that tirzepatide exerts anti-cancer effects in colorectal cancer cells by suppressing NF-kB-mediated inflammation, activating p53-dependent tumor suppression, and promoting CASP8-mediated apoptosis. The concurrent upregulation of c-Myc with p53 and CASP8 highlights potential context-dependent regulatory mechanisms. Overall, this study provides mechanistic insights into tirzepatide's modulation of oncogenic signaling pathways, supporting its potential role in colon cancer therapeutics.