Mol Biol Cell. 2023 Jan 25.
mbcE22070292
To survive poor nutritional conditions, tumor cells activate the unfolded protein response, which is composed of the IRE1, PERK and ATF6 arms, to maintain the homeostasis of the endoplasmic reticulum, where secretory and transmembrane proteins destined for the secretory pathway gain their correct three dimensional structure. The requirement of the IRE1 and PERK arms for tumor growth in nude mice is established. Here, we investigated the requirement for the ATF6 arm, which consists of ubiquitously expressed ATF6α and ATF6β, by constructing ATF6α-knockout, ATF6β-knockout and ATF6α/β-double knockout in HCT116 cells derived from human colorectal carcinoma. Results showed that these knockout cells grew similarly to wild-type cells in nude mice, contrary to expectations from our analysis of ATF6α-knockout, ATF6β-knockout and ATF6α/β-double knockout mice. We then found that the loss of ATF6α in HCT116 cells resulted in sustained activation of the IRE1 and PERK arms, in marked contrast to mouse embryonic fibroblasts, in which the loss of ATF6α is compensated for by ATF6β. Although IRE1-knockout in HCT116 cells unexpectedly did not affect tumor growth in nude mice, IRE1-knockout HCT116 cells with ATF6α knockdown grew significantly more slowly than wild-type or IRE1-knockout HCT116 cells. These results have unraveled the situation-dependent differential compensation strategies of ATF6α.