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Anastasis and the ER stress response: Solving the paradox of the unfolded protein response in cancer
1Department of Biochemistry and Molecular Biology, College of Medicine, University of the Philippines Manila, Ermita, Manila 1000, Philippines.
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.
Insights
Anastasis, or cell resurrection, is proposed to be the same mechanism as the endoplasmic reticulum (ER) stress response. This finding could impact cancer treatment by explaining tumor survival and regeneration after apoptosis.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Recent studies suggest a novel cell survival pathway termed anastasis (cell resurrection) at late-stage apoptosis.
- Biomarkers for anastasis are often linked to the endoplasmic reticulum (ER) stress response, a known survival mechanism.
- Distinguishing anastasis from ER stress is crucial for its acceptance and application in medicine.
Purpose of the Study:
- To propose that anastasis and the ER stress response are fundamentally the same biological mechanism.
- To provide a unified explanation for cell survival and regeneration following apoptotic triggers.
- To resolve the paradox of C/EBP homologous protein (CHOP)-induced tumor survival in cancer.
Main Methods:
- Conceptual analysis and synthesis of existing literature on anastasis and ER stress.
- Re-evaluation of biomarkers associated with late-stage apoptosis and cell survival.
- Integration of unfolded protein response (UPR) pathways with cancer cell survival strategies.
Main Results:
- Anastasis and ER stress response are proposed to be identical, differentiated only by the persistence of cellular stress.
- The C/EBP homologous protein (CHOP)-mediated survival in cancer is explained as an adaptive genetic alteration preceding enhanced ER stress.
- Anastatic cell recovery is redefined as the ER stress response occurring after the initiation of apoptosis.
Conclusions:
- Anastasis represents the ER stress response occurring in the post-apoptotic phase.
- This unified view offers a new perspective on cancer cell survival and potential therapeutic interventions.
- Understanding this mechanism could revolutionize translational medicine, particularly in oncology.
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