Abstract
Protective autophagy, a defensive response of cancer cells to chemotherapeutic stress, plays a critical role in the development of chemoresistance. Our previous research has demonstrated that the tight junction protein Claudin-6 (CLDN6) can induce autophagy and chemoresistance respectively. However, it remains unclear whether CLDN6 triggers protective autophagy under chemotherapeutic conditions. In this study, we focused on the role and mechanism of CLDN6 in inducing protective autophagy and promoting chemoresistance in breast cancer. We found that CLDN6 promoted chemoresistance by inducing protective autophagy in response to adriamycin (ADM) and paclitaxel (PTX). Mechanistically, CLDN6 interacted with LKB1 through its PDZ-binding motif, leading to the activation of AMPK/ULK1 signaling and subsequent promotion of protective autophagy. Notably, we discovered that chemotherapy increased CLDN6 expression through the reactive oxygen species (ROS)/GATA4 axis. Our results suggest that CLDN6 plays a pivotal role in breast cancer chemoresistance through protective autophagy, highlighting its potential as a therapeutic target to improve treatment outcomes of breast cancer patients.