Apoptosis is the regulated form of cell death utilized by metazoans to remove unneeded, damaged, or potentially deleterious cells. Certain manifestations of apoptosis may be associated with the proteolytic activity of caspases. These changes are often held as hallmarks of apoptosis in dying cells. Consequently, many regard caspases as the central effectors or executioners of apoptosis. However, this "caspase-centric" paradigm of apoptotic cell death does not appear to be as universal as once believed. In fact, during apoptosis the efficacy of caspases may be highly dependent on the cytotoxic stimulus as well as genetic and epigenetic factors. An ever-increasing number of studies strongly suggest that there are effectors in addition to caspases, which are important in generating apoptotic signatures in dying cells. These seemingly caspase-independent effectors may represent evolutionarily redundant or failsafe mechanisms for apoptotic cell elimination. In this review, we will discuss the molecular regulation of caspases and various caspase-independent effectors of apoptosis, describe the potential context and/or limitations of these mechanisms, and explore why the understanding of these processes may have relevance in cancer where treatment is believed to engage apoptosis to destroy tumor cells.
The apoptosis repressor with caspase recruitment domain (ARC) protein is known to suppress both intrinsic and extrinsic apoptosis. We previously reported that ARC expression is a strong, independent adverse prognostic factor in acute myeloid leukemia (AML). Here, we investigated the regulation and role of ARC in AML. ARC expression is upregulated in AML cells co-cultured with bone marrow-derived mesenchymal stromal cells (MSCs) and suppressed by inhibition of MAPK and PI3K signaling. AML patient samples with RAS mutations (N = 64) expressed significantly higher levels of ARC than samples without RAS mutations (N = 371) (P = 0.016). ARC overexpression protected and ARC knockdown sensitized AML cells to cytarabine and to agents that selectively induce intrinsic (ABT-737) or extrinsic (TNF-related apoptosis inducing ligand) apoptosis. NOD-SCID mice harboring ARC-overexpressing KG-1 cells had significantly shorter survival than mice injected with control cells (median 84 versus 111 days) and significantly fewer leukemia cells were present when NOD/SCID IL2R null mice were injected with ARC knockdown as compared to control Molm13 cells (P = 0.005 and 0.03 at 2 and 3 weeks, respectively). Together, these findings demonstrate that MSCs regulate ARC in AML through activation of MAPK and PI3K signaling pathways. ARC confers drug resistance and survival advantage to AML in vitro and in vivo, suggesting ARC as a novel target in AML therapy.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.