Elevated DNAJC5 expression is associated with poor prognosis in ovarian cancer patients.
Survival analysis indicates a strong link between high DNAJC5 levels and advanced International Federation of Gynecology and Obstetrics (FIGO) stage.
Patients with elevated DNAJC5 expression also display higher CA125 levels, a tumor marker in ovarian cancer.
Overexpression of DNAJC5 in A2780 cells results in increased resistance to cisplatin.
Cisplatin-resistant EOC cell lines show significantly higher DNAJC5 protein expression.
Knocking down DNAJC5 enhances cisplatin-induced cell death and reduces in resistant cells.
RNA sequencing reveals a strong correlation between DNAJC5 expression and endoplasmic reticulum stress.
Simplified
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, 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.
Key numbers
19.51 µM
Increase in IC value
IC value for A2780/ cells after treatment.
65%
Reduction in resistance
Decrease in IC value following -mediated knockdown of .
<0.001
Correlation with advanced
Statistical significance of expression in relation to .
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Declarations. Ethics declarations: The use of human tissues in this study was approved by the Ethics Committee of Nanjing First Hospital, Nanjing Medical University (No.KY20240822-KS-06). Written informed consent was obtained from the individual(s) for the publication of any data included in this article. The animal experiments were approved by the Animal Care and Use Committee of Nanjing First Hospital, Nanjing Medical University (No. DWSY-24143600). All of the methods were performed in accordance with relevant guidelines and regulations. All of the methods are reported in accordance with the ARRIVE guidelines. Competing interests: The authors declare no competing interests.
PubMed
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