LRP5 regulates chemoresistance via modulation of HIF-1α stability in colorectal cancer under hypoxia

Abstract LRP5 is a co-receptor in the Wnt signaling pathway and is generally known to promote tumor growth. However, its function under hypoxic conditions has not been clearly defined. Hypoxia and stabilization of hypoxia-inducible factor-1α (HIF-1α) play important roles in promoting metabolic adaptation and chemoresistance in colorectal cancer (CRC). In this study, we show that LRP5 attenuates hypoxia adaptation in CRC through a mechanism not fully explained by canonical Wnt/β-catenin signaling. LRP5 interacted with prolyl hydroxylase domain protein 2 (PHD2) and was associated with partial preservation of PHD-dependent HIF-1α hydroxylation capacity under hypoxia. At the phenotypic level, LRP5 overexpression reduced hypoxia-associated glycolytic and pro-angiogenic responses and enhanced drug sensitivity. Pharmacological inhibition of PHD activity by DMOG or IOX2, or expression of the degradation-resistant HIF-1α mutant (P402A/P564A), attenuated LRP5-associated HIF-1α regulation, supporting a PHD2-associated mechanism. LRP5 overexpression reduced the expression of the HIF-1α target gene GLUT1 and enhanced sensitivity to oxaliplatin, irinotecan, and 5-FU under hypoxia. These effects were observed without consistent changes in canonical Wnt/β-catenin signaling after LRP5 modulation, suggesting that the hypoxia-related function of LRP5 is not fully explained by β-catenin/TCF-dependent signaling alone. In patient datasets, high LRP5 and low HIF1A expression were associated with a trend toward better survival, especially in advanced-stage CRC. Our results identify a putative LRP5–PHD2–HIF-1α axis that regulates the hypoxic response, metabolic reprogramming, and chemoresistance in CRC. These findings suggest that LRP5 may function as a context-dependent suppressor of hypoxic adaptation and may serve as a potential biomarker of hypoxia-related chemoresistance in CRC.