ID1 confers cancer cell chemoresistance through STAT3/ATF6-mediated induction of autophagy

Abstract

AbstractChemoresistance is one of the major reasons leading to ovarian cancer high mortality and poor survival. Studies have shown that the alteration of cellular autophagy is associated with cancer cell chemoresistance. Here, we investigated whether the ovarian cancer chemoresistance is associated with the autophagy induced by the inhibitor of DNA binding 1 (ID1). By using gene overexpression or silencing, luciferase assay and human specimens, we show that ID1 induces high autophagy and confers cancer cell chemoresistance. The mechanistic study demonstrates that ID1 first activates the NF-κB signaling through facilitating the nuclear translocation of NF-κB p65, which strengthens the expression and secretion of IL-6 from cancer cells to subsequently activate the signal transducer and activator of transcription 3 (STAT3) through the protein phosphorylation at Y705. We further identified that STAT3 functions to promote the transcription of the activating transcription factor 6 (ATF6), which induces endoplasmic reticulum stress to promote cellular autophagy, granting cancer cell resistance to both cisplatin and paclitaxel treatment. Moreover, we found a significant correlation between the expression of ID1 and ATF6 in 1104 high grade serous ovarian cancer tissues, and that patients with the high expression of ID1 or ATF6 were resistant to platinum treatment and had the poor overall survival and progression-free survival. Thus, we have uncovered a mechanism in which ID1 confers cancer cell chemoresistance largely through the STAT3/ATF6-induced autophagy. The involved molecules, including ID1, STAT3, and ATF6, may have a potential to be targeted in combination with chemotherapeutic agents to improve ovarian cancer survival.