Heat-shock proteins (HSPs) play a crucial role in maintaining protein stability for cell survival during stress-induced insults. Overexpression of HSPs in cancer cells results in antiapoptotic activity contributing to cancer cell survival and restricting the efficacy of cytotoxic chemotherapy, which continues to play an important role in the treatment of many cancers, including triple-negative breast cancer (TNBC). First-line therapy for TNBC includes anthracycline antibiotics, which are associated with serious dose-dependent side effects and the development of resistance. We previously identified YDJ1, which encodes a heat-shock protein 40 (HSP40), as an important factor in the cellular response to anthracyclines in yeast, with mutants displaying over 100-fold increased sensitivity to doxorubicin. In humans, the DNAJA HSP40s are homologues of YDJ1. To determine the role of DNAJAs in the cellular response to cytotoxic drugs, we investigated their ability to rescue ydj1Δ mutants from exposure to chemotherapeutic agents. Our results indicate that DNAJA1 and DNAJA2 provide effective protection, while DNAJA3 and DNAJA4 did not. The level of complementation was also dependent on the agent used, with DNAJA1 and DNAJA2 rescuing the ydj1Δ strain from doxorubicin, cisplatin, and heat shock. DNAJA3 and DNAJA4 did not rescue the ydj1Δ strain and interfered with the cellular response to stress when expressed in wild type background. DNAJA1 and DNAJA2 protect the cell from proteotoxic damage caused by reactive oxygen species (ROS) and are not required for repair of DNA double-strand breaks. These data indicate that the DNAJAs play a role in the protection of cells from ROS-induced cytotoxic stress.
Anthracyclines are frequently used to treat many cancers including triple negative breast cancer, which is commonly observed in African-American women (AA), and tend to be more aggressive, carry worse prognoses, and are harder to manage because they lack molecular targets. Although effective, anthracyclines use can be limited by serious side effects and eventually the development of drug resistance. In S. cerevisiae, mutants of HOM6 display hypersensitivity to doxorubicin. HOM6 is required for synthesis of threonine and interruption of the pathway leads to accumulation of the threonine intermediate L-aspartate-semialdehyde. This intermediate may synergize with doxorubicin to kill the cell. In fact, deleting HOM3 in the first step, preventing the pathway to reach the HOM6 step, rescues the sensitivity of the hom6 strain to doxorubicin. Using several S. cerevisiae strains (wild type, hom6, hom3, hom3hom6, ydj1, siz1, and msh2), we determined their sensitivity to aldehydes and to their combination with doxorubicin, cisplatin, and etoposide. Combination of formaldehyde and doxorubicin was most effective at reducing cell survival by 31-fold–39-fold (in wild type cells) relative to doxorubicin and formaldehyde alone. This effect was dose dependent on doxorubicin. Cotreatment with formaldehyde and doxorubicin also showed increased toxicity in anthracycline-resistant strains siz1 and msh2. The hom6 mutant also showed sensitivity to menadione with a 2.5-fold reduction in cell survival. The potential use of a combination of aldehydes and cytotoxic drugs could potentially lead to applications intended to enhance anthracycline-based therapy.
Triple Negative Breast Cancer (TBNC) lacking biological targets results in limited therapeutic options and leads to high mortality rates. The last therapy is Doxorubicin (Cytotoxic chemotherapeutic drug), an anti-tumor therapeutic alternative; which has bad side effects (cardiotoxicity), due to dose dependence, leading to drug resistance. There are three primary mechanisms of action for doxorubicin: Intercalation into DNA, which directly affects transcription and replication. Inhibition of topoisomerase II activity during the double-strand break, which prevents the binding portion of the ligation reaction that topoisomerase II catalyzes, by stabilizing the DNA-topoisomerase II alpha complex. Lastly, generating free radicals as it cycles between its quinone and semi-quinone structures during metabolic reactions, which generates reactive oxygen species. Research says heat shock proteins (HSPs) help to protect cells using heat-shock response. Several HSPs have been tested, with limited knowledge of HSP40s (DNAJAs). We will determine which DNAJA (1 to 4) assists in the survival response to doxorubicin by observing the domains and expression of the proteins being exposed to chemotherapy. The J domain has shown to be a critical area for increasing cell sensitivity while reducing cardiotoxicity. Expression levels were analyzed via RT-PCR and Western Blots, and relevant domains via COSMIC database. In conclusion the first step to reducing cardiotoxicity with chemotherapeutics is by modifying HSP40 functionality in human cancer cells, providing an alternative to hypersensitization to chemotherapy, allowing for lower dosage with less side effects. Citation Format: Devon Freeny. Changes in the expression levels of DNAJAs in triple negative breast cancer cells exposed to cytotoxic chemotherapy [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-016.
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