Leptin increases chemosensitivity by inhibiting CPT1B in colorectal cancer cells.

Abstract

Background: Chemoresistance is a major cause of treatment failure in advanced colorectal cancer (CRC), severely impacting patient survival and quality of life. While conventional chemotherapy regimens can somewhat control tumor progression, their effectiveness is frequently compromised by the development of drug resistance in cancer cells. The aim of this study is to verify and elucidate the specific mechanisms by which leptin enhances chemosensitivity in CRC, providing valuable insights for the development of new combination chemotherapy options.

Methods: We examined the link between CRC chemoresistance and fatty-acid metabolism driven by the high expression of carnitine palmitoyltransferase-1b (CPT1B) through an integrated approach combining bioinformatics and clinical sample analysis. In vitro and in vivo experiments were conducted to evaluate the effect of leptin, an adipocyte-derived cytokine, on CRC cells' response to cisplatin.

Results: Leptin significantly enhanced CRC cells' chemosensitivity to cisplatin by downregulating CPT1B expression, thereby disrupting the fatty-acid oxidation pathways that support drug resistance. In mouse models, the coadministration of leptin and cisplatin resulted in notable reductions in tumor size and weight compared to cisplatin alone, underscoring leptin's potential to enhance chemotherapy efficacy.

Conclusions: These findings indicate that leptin, through modulation of CPT1B, may serve as a promising adjunct to chemotherapy for CRC, addressing the challenge of chemoresistance and improving therapeutic outcomes. The leptin-CPT1B axis may be potential therapeutic target, providing new avenues for CRC treatment strategies aimed at overcoming drug resistance.