FZD5 induces chemoresistance through ALDH1A1 in ovarian cancer

Chemoresistance is associated with tumor relapse and unfavorable prognosis. Multiple mechanisms underlying chemoresistance have been elucidated, including stemness and DNA damage repair. Here, the involvement of WNT receptor FZD5 in ovarian cancer (OC) chemoresistance was investigated. Function studies on OC cells showed that FZD5 contributes to epithelial phenotype maintenance, growth, stemness, homologous recombination (HR) repair, and chemoresistance. Mechanistically, FZD5 modulates the expression of ALDH1A1, a functional marker for cancer stem-like cells (CSCs), in a β-catenin-dependent manner. ALDH1A1 activates Akt signaling, further upregulating RAD51 and BRCA1 to promote HR repair. Taken together, these findings demonstrate that FZD5-ALDH1A1-Akt pathway is responsible for the survival of OC cells, and targeting this pathway can sensitize OC cells to DNA-damaging therapy.