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Targeting Human DNAJAs for Sensitization to Chemotherapeutic Agents
Author(s) -
Whitmore Aurellia
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.996.5
Subject(s) - doxorubicin , medicine , cancer research , etoposide , cancer , triple negative breast cancer , cytotoxic t cell , breast cancer , druggability , cancer cell , chemotherapy , pharmacology , biology , gene , biochemistry , in vitro
Purpose Breast cancer is the second leading cause of cancer death among women in the US, with 20% of breast cancers being Triple Negative Breast Cancer (TNBC) which occur more often in African Americans and younger women. Despite considerable advances in targeted cancer therapy, many tumors including TNBC tumors either lack druggable targets or they lose them during cancer progression. For this reason, cytotoxic chemotherapy aimed at cellular proliferation continues to play an important role in the treatment of many neoplasias. First line of therapy for TNBC include agents such as anthracycline antibiotics, which albeit being effective are associated with serious side‐effects. Furthermore, drug resistance can develop during the course of treatment, which cannot be overcome by increasing the therapeutic dose. Preliminary studies in the eukaryotic model organism S. cerevisiae , have identified YDJ1 , which encodes a heat‐shock 40 protein (HSP40), as an important factor in the cellular response to chemotherapeutic agent doxorubicin. Mutants of the YDJ1 gene display >100‐fold increased sensitivity to doxorubicin. In mammalian cells, the DNAJA group of HSP40 proteins, which includes DNAJA1, DNAJA2, DNAJA3 and DNAJA4, are more closely related to YDJ1 . To determine the role of DNAJAs and target them for sensitization in the cellular response to cytotoxic drugs, we investigated their ability to rescue ydj1 mutants from exposure to chemotherapeutic agents. Design Methods Mutant strains complemented by the DNAJAs were exposed to chemotherapy agents: doxorubicin, and etoposide, as well as oxidative stress agent menadione. Results Our results indicate that the different DNAJAs provide distinct levels of protection, with DNAJA1 and DNAJA2 being more effective at complementation while DNAJA3 and DNAJA4 being less effective. In addition, the level of complementation was also dependent on the agent used. Conclusion Complementation with DNAJA2 was effective to rescue the response to cellular stress of doxorubicin and menadione, with no major contribution in the response to etoposide. These data indicate that the DNAJAs play a role in the protection of cells from cytotoxic stress and may serve as targets to hypersensitize cells to cancer therapy, allowing for treatment with lower dose with a concomitant reduction of side effects. Support or Funding Information This research is funded by the National Institute on Minority Health Disparities of the National Institute of Health under Award# P20MD006738, NIH‐RCMI Grant# 2G12RR003020 and the NMHHD, NIH 8G12MD007582‐28.