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.

A Retrospective on eIF2A—and Not the Alpha Subunit of eIF2

“…The authors showed that the loss of ISR increases paclitaxel-mediated cell death and that eIF2A is one of the key and essential factors for cancer cell survival under the conditions of paclitaxel-mediated ISR [102]. Knockdown of eIF2A substantially impaired cancer cell survival under the ISR [102]. The authors also found that elevated levels of eIF2A mRNA in patients with breast cancer are correlated with poor prognosis [102].…”

“…Several additional recent reports have shown that eIF2A has specific functions during the ISR as well as cancer progression [102,103]. Chen et al demonstrated that eIF2A promotes cell survival during paclitaxel-mediated ISR in vitro and in vivo [102]. Paclitaxel is one of the major chemotherapy drugs for breast cancer treatment and its application is associated with strong ISR [102].…”

“…Chen et al demonstrated that eIF2A promotes cell survival during paclitaxel-mediated ISR in vitro and in vivo [102]. Paclitaxel is one of the major chemotherapy drugs for breast cancer treatment and its application is associated with strong ISR [102]. The ISR, however, is believed to be critical for cancer cell survival during stress stimuli and has been implicated in the resistance to cancer therapeutics [102].…”

“…Paclitaxel is one of the major chemotherapy drugs for breast cancer treatment and its application is associated with strong ISR [102]. The ISR, however, is believed to be critical for cancer cell survival during stress stimuli and has been implicated in the resistance to cancer therapeutics [102]. The authors showed that the loss of ISR increases paclitaxel-mediated cell death and that eIF2A is one of the key and essential factors for cancer cell survival under the conditions of paclitaxel-mediated ISR [102].…”

“…The ISR, however, is believed to be critical for cancer cell survival during stress stimuli and has been implicated in the resistance to cancer therapeutics [102]. The authors showed that the loss of ISR increases paclitaxel-mediated cell death and that eIF2A is one of the key and essential factors for cancer cell survival under the conditions of paclitaxel-mediated ISR [102]. Knockdown of eIF2A substantially impaired cancer cell survival under the ISR [102].…”