EIF2A promotes cell survival during paclitaxel treatment in vitro and in vivo.

Abstract

The integrated stress response (ISR) is critical for cancer cell survival during stress stimuli and has been implicated in the resistance to cancer therapeutics, in which the mechanism, however, is poorly understood. Here, we showed that paclitaxel, the major chemotherapy drug for breast cancer, induced ISR and phosphorylated ser51 residue of EIF2S1 by EIF2AK3 and EIF2AK4. When exposed to paclitaxel, cancer cells activated the EIF2AK3/EIF2AK4-pEIF2S1-ATF4 axis and maintained redox homoeostasis by inducing expression of the major antioxidant enzymes HMOX1, SHMT2 and SLC7A11. Paclitaxel-mediated cell death was significantly increased following loss of ISR or ATF4 expression. This sensitizing effect could be partially rescued by Trolox, a ROS scavenger. We demonstrated that the alternative initiation factor EIF2A was essential for cancer cell survival after paclitaxel-mediated ISR both in vitro and in vivo. Moreover, patients with breast cancer exhibited higher ISR after chemotherapy, and the elevated mRNA levels of HMOX1, SHMT2 and EIF2A were correlated with poor prognosis. Collectively, our findings reveal a novel mechanism for paclitaxel resistance and suggest that targeting EIF2A combined with ISR agonist may be a potential treatment regimen to overcome drug resistance for breast cancer.

• Authors: Lin Chen, Jiang He, Jianhua Zhou, Zhi Xiao, Nianhua Ding, Yumei Duan, Wenzheng Li, Lun-Quan Sun
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 23 Issue 9 Pg. 6060-6071 (09 2019) ISSN: 1582-4934 [Electronic] England
• PMID: 31211507 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Chemical References

• ATF4 protein, human
• Amino Acid Transport System y+
• EIF2S1 protein, human
• Eukaryotic Initiation Factor-2
• SLC7A11 protein, human
• Activating Transcription Factor 4
• HMOX1 protein, human
• Heme Oxygenase-1
• Glycine Hydroxymethyltransferase
• SHMT protein, human
• EIF2AK3 protein, human
• EIF2AK4 protein, human
• Protein Serine-Threonine Kinases
• eIF-2 Kinase
• Paclitaxel

Topics

• Activating Transcription Factor 4 (genetics)
• Amino Acid Transport System y+ (genetics)
• Breast Neoplasms (drug therapy, genetics, pathology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Drug Resistance, Neoplasm (genetics)
• Eukaryotic Initiation Factor-2 (genetics)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Glycine Hydroxymethyltransferase (genetics)
• Heme Oxygenase-1 (genetics)
• Heterografts
• Humans
• Paclitaxel (adverse effects, pharmacology)
• Protein Serine-Threonine Kinases (genetics)
• Signal Transduction (drug effects)
• eIF-2 Kinase (genetics)