Activation of the eIF2α/ATF4 axis drives triple-negative breast cancer radioresistance by promoting glutathione biosynthesis
Xupeng Bai,
Jie Ni,
Julia Beretov,
Valerie C. Wasinger,
Shanping Wang,
Ying Zhu,
Peter Graham,
Yong Li
Affiliations
Xupeng Bai
St George and Sutherland Clinical School, Faculty of Medicine, UNSW Sydney, Kensington, NSW, 2052, Australia; Cancer Care Centre, St. George Hospital, Kogarah, NSW, 2217, Australia
Jie Ni
St George and Sutherland Clinical School, Faculty of Medicine, UNSW Sydney, Kensington, NSW, 2052, Australia; Cancer Care Centre, St. George Hospital, Kogarah, NSW, 2217, Australia
Julia Beretov
St George and Sutherland Clinical School, Faculty of Medicine, UNSW Sydney, Kensington, NSW, 2052, Australia; Cancer Care Centre, St. George Hospital, Kogarah, NSW, 2217, Australia; Anatomical Pathology, NSW Health Pathology, St. George Hospital, Kogarah, NSW, 2217, Australia
Valerie C. Wasinger
Bioanalytical Mass Spectrometry Facility, Mark Wainwright Analytical Centre, UNSW Sydney, Kensington, NSW, 2052, Australia; School of Medical Science, UNSW Sydney, Kensington, NSW, 2052, Australia
Shanping Wang
School of Biomedicine and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, 510006, China
Ying Zhu
St George and Sutherland Clinical School, Faculty of Medicine, UNSW Sydney, Kensington, NSW, 2052, Australia; Cancer Care Centre, St. George Hospital, Kogarah, NSW, 2217, Australia
Peter Graham
St George and Sutherland Clinical School, Faculty of Medicine, UNSW Sydney, Kensington, NSW, 2052, Australia; Cancer Care Centre, St. George Hospital, Kogarah, NSW, 2217, Australia
Yong Li
St George and Sutherland Clinical School, Faculty of Medicine, UNSW Sydney, Kensington, NSW, 2052, Australia; Cancer Care Centre, St. George Hospital, Kogarah, NSW, 2217, Australia; School of Basic Medicine, Zhengzhou University, Zhengzhou, 450001, China; Corresponding author. Level 2, Research and Education Centre, St George Hospital, 4-10 South St, Kogarah, NSW, 2217, Australia.
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. Radiotherapy is an effective option for the treatment of TNBC; however, acquired radioresistance is a major challenge to the modality. In this study, we show that the integrated stress response (ISR) is the most activated signaling pathway in radioresistant TNBC cells. The constitutive phosphorylation of eIF2α in radioresistant TNBC cells promotes the activation of ATF4 and elicits the transcription of genes implicated in glutathione biosynthesis, including GCLC, SLC7A11, and CTH, which increases the intracellular level of reduced glutathione (GSH) and the scavenging of reactive oxygen species (ROS) after irradiation (IR), leading to a radioresistant phenotype. The cascade is significantly up-regulated in human TNBC tissues and is associated with unfavorable survival in patients. Dephosphorylation of eIF2α increases IR-induced ROS accumulation in radioresistant TNBC cells by disrupting ATF4-mediated GSH biosynthesis and sensitizes them to IR in vitro and in vivo. These findings reveal ISR as a vital mechanism underlying TNBC radioresistance and propose the eIF2α/ATF4 axis as a novel therapeutic target for TNBC treatment.
