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

Sep 24, 2026

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Epithelial ovarian cancer relies on platinum-based chemotherapy, yet primary or acquired resistance sharply worsens survival. This study investigates the role of DNAJC5 in cisplatin resistance, integrating TCGA survival analysis, immunohistochemistry, and functional assays. DNAJC5 overexpression associates with poor prognosis, advanced FIGO stage, and higher CA125, while knockdown increases cisplatin-induced apoptosis and suppresses autophagy. RNA sequencing links DNAJC5 to endoplasmic reticulum stress, with BiP-IRE1α-XBP1 upregulation driving autophagy and enhanced cisplatin resistance, supported by drug and in vivo validation.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages17

Reading Time43 min

AccessFree to download

Background

Platinum chemotherapy resistance in epithelial ovarian cancer

Autophagy and ER stress as resistance mechanisms

Study focus and approach

Clinical correlation using TCGA and immunohistochemistry

Cellular function assays in cisplatin-sensitive and resistant lines

Mechanistic exploration via RNA sequencing and signaling validation

Key findings

DNAJC5 expression predicts poor prognosis and aggressive disease features

DNAJC5 modulates cisplatin response and autophagy

BiP-IRE1α-XBP1 pathway links ER stress to autophagy and resistance

Validation and conclusion

Pharmacologic and in vivo support for the proposed mechanism

Summary of DNAJC5’s role in cisplatin resistance

[www. nature.com/scientificreports](www. nature.com/scientificreports) OPEN DNAJC5 promotes cisplatin resistance in epithelial ovarian cancer by autophagy induced by the BiP/IRE1α/XBP1 endoplasmic reticulum stress pathway Shijia Huang1,5, Ling Chen2,5, Yirong Chen1, Siyan Lu1, Bowen Yang1, Ya Chen2, Wei Zhao3 & Shuli Zhao1,4􀀍 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 theTCGA 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 inA2780 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. Keywords Epithelial ovarian cancer, Cisplatin resistance, DNAJC5, Endoplasmic reticulum stress, Autophagy Abbreviations DDPEOC DNAJC5 Hsp40 HCC Cisplatin Epithelial ovarian cancer DnaJ Heat Shock Protein Family (Hsp40) Member C5 Heat Shock Protein Family Hepatocellular carcinoma 1General Clinical Research Center, Nanjing First Hospital, China Pharmaceutical University, Nanjing, Jiangsu, China. 2Department of Pathology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China. 3Department of Pathology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China. 4General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China. 5Shijia Huang and Ling Chen contributed equally to this work. 􀀍 email: [shulizhao79@njmu.edu.cn](shulizhao79@njmu.edu.cn) [www. nature.com/scientificreports/](www. nature.com/scientificreports/) IHCCCK-8 BiPIRE1α XBP1 XBP1u XBP1s LC3 ER stress CMAHsc70 PERK ATF6 UPR Hsp70 DMEM STREDTA DAB IRS FIGOCA125 siRNAGO PBS FBS FITC PI BCA 5×SDS-PAGE PVDF TBSTHRPECL GAPDHp-IRE1α ATF4 qPCR NIH HEPATCGA IC 50 TDP-43 BECN1 RNA-seq CQ Immunohistochemistry Cell Counting Kit-8 Heavy chain binding protein Inositol-requiring enzyme 1α X-box binding protein 1 gene The non-splicing form of X-box binding protein 1 The spliced form of X-box binding protein 1 Microtubule-associated protein 1 light chain 3 Endoplasmic reticulum stre

FAQs

How is DNAJC5 linked to cisplatin resistance in epithelial ovarian cancer?

Higher DNAJC5 expression is associated with poor prognosis and more aggressive clinical features. In cell models, DNAJC5 overexpression increases cisplatin resistance, while knockdown enhances cisplatin-induced apoptosis and reduces autophagy in resistant cells.

What experimental evidence supports DNAJC5’s role in autophagy?

The study reports that DNAJC5 knockdown inhibits autophagy in cisplatin-resistant A2780/DDP cells, supported by apoptosis staining (Annexin V/PI), viability and clonogenic assays (CCK-8, colony formation), and Western blot analysis.

Which pathway mediates the effect of DNAJC5 on cisplatin resistance?

Mechanistic work connects DNAJC5 with endoplasmic reticulum stress and upregulation of the BiP-IRE1α-XBP1 axis. This signaling increase correlates with higher autophagy levels and stronger cisplatin resistance, validated with pathway-linked experiments including hydroxychloroquine and 4µ8C and in vivo studies.

Sep 24, 2026

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