Anastasis and the ER stress response: Solving the paradox of the unfolded protein response in cancer

Abstract

In recent years, studies have suggested a novel pathway for cell survival, which faces scientific skepticism and interest in its concept of cell ‘resurrection’ – that is, the anastasis of cells at late-stage apoptosis. While biomarkers have been discovered, many of these are related to the endoplasmic reticulum (ER) stress response – acting also to promote cell survival in the presence of perturbation. The promises of anastasis, if accepted, will greatly impact translational medicine especially in the treatment of cancer, since apoptosis is generally irreversible in the late stages, and chemotherapy is performed to maximize tumor death and minimize off-target effects. As with all new concepts, there is a need to demarcate anastasis from a well-studied survival mechanism – the ER stress response – if the concept is to progress any further. In this article, it is proposed that anastasis and the ER stress response are one and the same mechanism, demarcated only by the presence of persistent stress. Further, anastasis solves the paradox of the unfolded protein response (UPR) in cancer by providing rationale in C/EBP homologous protein (CHOP)-induced tumor survival, such that CHOP-mediated apoptosis initiates genetic alterations in favor of its survival. After which, the cell regenerates through an enhanced ER stress response. Hence, anastatic cell recovery is the ER stress response post-apoptosis.