DNAJC5 promotes cisplatin resistance in epithelial ovarian cancer by autophagy induced by the BiP/IRE1α/XBP1 endoplasmic reticulum stress pathway

Ovarian Cancer is the most lethal gynecological malignancy, with platinum-based chemotherapy serving as the standard first-line treatment. However, the emergence of primary or acquired resistance significantly compromises patient survival. Among the mechanisms contributing to chemotherapy resistance, Autophagy plays a crucial role. DnaJ heat shock protein family (HSP40) member C5 (DNAJC5) is a key regulator of nervous system function. Recent studies suggest that DNAJC5 may also be involved in tumor progression. Based on this, we aimed to investigate the role of DNAJC5 in epithelial ovarian Cancer (EOC) chemotherapy resistance. Survival analysis of the TCGA database revealed a strong association between elevated DNAJC5 expression and poor prognosis in ovarian Cancer patients. Immunohistochemistry (IHC) and statistical analyses demonstrated that patients with high DNAJC5 expression frequently presented with advanced International Federation of Gynecology and Obstetrics (FIGO) stage and elevated CA125 levels. Functional experiments showed that overexpression of DNAJC5 in A2780 cells markedly increased resistance to cisplatin (DDP). Moreover, cisplatin-resistant EOC cell lines (A2780/DDP) exhibited high levels of DNAJC5 protein expression. Conversely, DNAJC5 knockdown enhanced cisplatin-induced Apoptosis and inhibited Autophagy in A2780/DDP cells, as confirmed by Annexin V/PI staining, CCK-8 assays, colony formation assays, and Western blot analysis. Further mechanistic investigations using RNA Sequencing identified a strong correlation between DNAJC5 expression and endoplasmic reticulum (ER) stress. Western blot analysis confirmed that DNAJC5 overexpression upregulated BiP-IRE1α-XBP1 protein expression, which was significantly associated with both increased Autophagy levels and enhanced DDP resistance. These findings were further supported by validation experiments using hydroxychloroquine(CQ) and 4µ8C, as well as in vivo animal studies. In conclusion, this study demonstrates that DNAJC5 overexpression promotes DDP resistance in EOC by modulating Autophagy through the BiP-IRE1α-XBP1 signaling pathway.

Autophagy; Cisplatin resistance; DNAJC5; Endoplasmic reticulum stress; Epithelial ovarian cancer.