tLivin Displays Flexibility by Promoting Alternative Cell Death Mechanisms

Abstract

Livin is a member of the Inhibitor of Apoptosis (IAP) protein family that inhibits apoptosis triggered by a variety of stimuli. We previously demonstrated that while Livin inhibits caspase activity, caspases can cleave Livin to produce a truncated protein, tLivin and that this newly formed tLivin paradoxically induces cell death. However to date, the mechanism of tLivin-induced cell death is not fully understood. In this study, we set out to characterize the form of cell death mediated by tLivin. Here we demonstrate that, unlike most death-promoting proteins, tLivin is a flexible inducer of cell death capable of promoting necrosis or apoptosis in different cell lines. The unusual flexibility of tLivin is displayed by its ability to activate an alternative form of cell death when apoptosis is inhibited. Thus, tLivin can promote more than one form of cell death in the same cell type. Interestingly, in cells where tLivin induces necrosis, deletion of the caspase binding BIR domain results in tLivin-induced apoptosis, suggesting the BIR domain can potentially hamper the ability of tLivin to induce apoptosis. We further elucidate that tLivin activates the JNK pathway and both tLivin-induced apoptosis and necrosis are partially mediated by JNK activity. Acquired resistance to apoptosis, common in many tumors, impinges on the efficiency of conventional anti-cancer agents that function primarily by inducing apoptosis. The ability of tLivin to induce death of apoptosis-compromised cells makes it an attractive candidate for targeted cancer therapy.

Clearance of autophagy-associated dying retinal pigment epithelial cells – a possible source for inflammation in age-related macular degeneration

“…In addition, AnxV/PI double positivity is a sign of late apoptosis, primary or secondary necrosis. 50 , 51 After 2 h of 1 mM H 2 O 2 treatment, the percentage of living ARPE-19 cells, compared with the untreated control ones, significantly decreased from 91.4±1.7% to 28.6±14.2%. In case of hRPE cells, the ratio of living cells changed from 87.1±4.9% to 51.6±3.6%.…”

Silencing of Livin inhibits tumorigenesis and metastasis via VEGF and MMPs pathway in lung cancer

“…Increasing number of studies reveal that Livin can inhibit apoptosis induced by a variety of stimulus, while it is specifically cleaved by caspases on a strong apoptotic stimulus to produce a truncated protein which inversely harbors the death-promoting activity, indicating a dual role of Livin in cell biology (10,(24)(25)(26). The subcellular localization of Livin can be an alternative mechanism that regulates the balance between the anti-and pro-apoptotic activity of Livin (27).…”

BIRC7 (baculoviral IAP repeat containing 7)

“…However, once the BIR domain was deleted from tlivin, 293T cells failed to express JNK, suggesting a role for BIR in activation of this pathway. In MelA1 cells, when these were treated with a pan-caspase inhibitor, t-livin-induced cell death was only partially abrogated, implying an aptitude of t-livin to induce cell death in situations where the apoptotic process is compromised (Shiloach et al, 2014).…”