Loss of ATF6α in a human carcinoma cell line is compensated not by its paralogue ATF6β but by sustained activation of the IRE1 and PERK arms for tumor growth in nude mice.

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 (KO), ATF6β-KO, and ATF6α/β-double KO (DKO) in HCT116 cells derived from human colorectal carcinoma. Results showed that these KO cells grew similarly to wild-type (WT) cells in nude mice, contrary to expectations from our analysis of ATF6α-KO, ATF6β-KO, and ATF6α/β-DKO 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-KO in HCT116 cells unexpectedly did not affect tumor growth in nude mice, IRE1-KO HCT116 cells with ATF6α knockdown grew significantly more slowly than WT or IRE1-KO HCT116 cells. These results have unraveled the situation-dependent differential compensation strategies of ATF6α.