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Updated: Dec 11, 2025
Using Caenorhabditis elegans to Screen for Tissue-Specific Chaperone Interactions
Published on: June 7, 2020
Chemogenomic screening identifies the Hsp70 co-chaperone DNAJA1 as a hub for anticancer drug resistance
Nitika1, Jacob S Blackman1, Laura E Knighton1
1Department of Biological Sciences, University of North Carolina Charlotte, Charlotte, NC, 28223, USA.
Abstract:
Heat shock protein 70 (Hsp70) is an important molecular chaperone that regulates oncoprotein stability and tumorigenesis. However, attempts to develop anti-chaperone drugs targeting molecules such as Hsp70 have been hampered by toxicity issues. Hsp70 is regulated by a suite of co-chaperone molecules that bring "clients" to the primary chaperone for efficient folding. Rather than targeting Hsp70 itself, here we have examined the feasibility of inhibiting the Hsp70 co-chaperone DNAJA1 as a novel anticancer strategy. We found DNAJA1 to be upregulated in a variety of cancers, suggesting a role in malignancy. To confirm this role, we screened the NIH Approved Oncology collection for chemical-genetic interactions with loss of DNAJA1 in cancer. 41 compounds showed strong synergy with DNAJA1 loss, whereas 18 dramatically lost potency. Several hits were validated using a DNAJA1 inhibitor (116-9e) in castration-resistant prostate cancer cell (CRPC) and spheroid models. Taken together, these results confirm that DNAJA1 is a hub for anticancer drug resistance and that DNAJA1 inhibition is a potent strategy to sensitize cancer cells to current and future therapeutics. The large change in drug efficacy linked to DNAJA1 suggests a personalized medicine approach where tumor DNAJA1 status may be used to optimize therapeutic strategy.
Insights
Targeting the DNAJA1 co-chaperone, not Hsp70, offers a novel anticancer strategy. Inhibiting DNAJA1 sensitizes cancer cells to therapies and may enable personalized medicine approaches.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Heat shock protein 70 (Hsp70) is a molecular chaperone crucial for oncoprotein stability and cancer development.
- Targeting Hsp70 directly for cancer therapy has faced challenges due to toxicity.
- Hsp70 function is modulated by co-chaperones, presenting an alternative therapeutic avenue.
Purpose of the Study:
- To investigate the potential of inhibiting the Hsp70 co-chaperone DNAJA1 as a novel anticancer strategy.
- To determine if DNAJA1 is upregulated in various cancers and contributes to malignancy.
- To explore the therapeutic implications of DNAJA1 inhibition in overcoming anticancer drug resistance.
Main Methods:
- Screened the NIH Approved Oncology collection for chemical-genetic interactions with DNAJA1 loss in cancer models.
- Validated synergistic and antagonistic drug responses associated with DNAJA1 loss.
- Tested a DNAJA1 inhibitor (116-9e) in castration-resistant prostate cancer (CRPC) cell and spheroid models.
Main Results:
- DNAJA1 was found to be upregulated in multiple cancer types, indicating its role in malignancy.
- 41 compounds demonstrated strong synergy with DNAJA1 loss, while 18 lost potency.
- DNAJA1 inhibition sensitized CRPC cells to therapeutic agents, confirming its role in drug resistance.
Conclusions:
- DNAJA1 is a critical regulator of anticancer drug resistance.
- Inhibiting DNAJA1 is a viable strategy to enhance the efficacy of existing and novel cancer therapeutics.
- Tumor DNAJA1 status could guide personalized medicine strategies for optimized cancer treatment.
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