Obesity results from an imbalance between caloric intake and energy expenditure, and it is highly associated with colorectal
carcinogenesis and therapeutic resistance in patients with
colorectal cancer (CRC). Dysregulation of
adipokine production in
obesity has been reported to cause malignant behaviors in CRC.
Leptin, which is the principal
hormone secreted by adipocytes and an
obesity-associated
adipokine, is significantly overexpressed in CRC tissues. However, the effect of
leptin on chemoresistance in CRC is unclear. Therefore, the aim of this study was to clarify the role of
leptin and the underlying mechanisms in mediating
5-fluorouracil (5-FU) resistance in CRC. We used
palmitate to artificially generate obese adipocytes. As expected,
lipid accumulation was significantly increased in obese adipocytes. We demonstrated that CRC cells incubated with
conditioned media (CM) harvested from obese adipocytes were associated with increased resistance to
5-FU. Notably, this increase in resistance to
5-FU was through the elevated production and secretion of
leptin.
Leptin could further stimulate the expression of AXL and activate its downstream signaling molecule, PLCĪ³, thereby resulting in an increased expression of
p-glycoprotein (P-gp) in CRC cells. Mechanistically,
leptin induced AXL expression via the inhibition of AMPK and subsequent increase in YAP activation and nuclear translocation. In addition, nuclear YAP interacted with TEAD and promoted the occupancy of TEAD on the AXL promoter, thereby stimulating AXL promoter activity after
leptin treatment. Furthermore,
leptin neutralization rescued the sensitivity of CRC
tumors to
5-FU in mice fed on a high-fat diet (HFD). These results indicated that
leptin mediated
5-FU resistance through YAP-dependent AXL overexpression in CRC.