Evaluation of the Role of Human DNAJAs in the Response to Cytotoxic Chemotherapeutic Agents in a Yeast Model System.

Aurellia Whitmore,Hernan Flores-Rozas,Devon Freeny,Jana S Miles,Willie M Graham,Samantha J Sojourner

doi:10.1155/2020/9097638

Abstract

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.

Highlights

Despite advances in targeted therapy of cancer, cytotoxic chemotherapy remains an essential therapeutic alternative
Some cancers lack therapeutic targets or lose them during cancer progression and rely solely on cytotoxic chemotherapy as a means of treatment. is approach is used for triple-negative breast cancer (TNBC), which lacks the estrogen, progesterone, and HER2 receptors required for targeted therapy [1], limiting its treatment to the use of cytotoxic chemotherapy such as anthracycline antibiotics [2]
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 did not complement

Summary

Introduction

Despite advances in targeted therapy of cancer, cytotoxic chemotherapy remains an essential therapeutic alternative. Targeted and cytotoxic chemotherapy are two distinctive modes of cancer treatment with each associating to certain benefits and limitations. Targeted therapies are used to kill tumor cells based on the presence of cancer-specific molecules, whereas cytotoxic chemotherapy has a nonselective mechanism of action aimed at proliferating cells. Both approaches may result in therapeutic resistance. Is approach is used for triple-negative breast cancer (TNBC), which lacks the estrogen, progesterone, and HER2 receptors required for targeted therapy [1], limiting its treatment to the use of cytotoxic chemotherapy such as anthracycline antibiotics [2]. Anthracycline antibiotics, doxorubicin, are one of the most common and effective antineoplastic agents used in treatment of a large number of malignancies

Methods

Results

Conclusion