Voltage dependent anion channel-1 regulates death receptor mediated apoptosis by enabling cleavage of caspase-8

Queen's University Belfast, Centre for Cancer Research and Cell Biology, Belfast, UK.
BMC Cancer (Impact Factor: 3.36). 07/2010; 10(1, article 380):380. DOI: 10.1186/1471-2407-10-380
Source: PubMed


Activation of the extrinsic apoptosis pathway by tumour necrosis factor related apoptosis inducing ligand (TRAIL) is a novel therapeutic strategy for treating cancer that is currently under clinical evaluation. Identification of molecular biomarkers of resistance is likely to play an important role in predicting clinical anti tumour activity. The involvement of the mitochondrial type 1 voltage dependent anion channel (VDAC1) in regulating apoptosis has been highly debated. To date, a functional role in regulating the extrinsic apoptosis pathway has not been formally excluded.
We carried out stable and transient RNAi knockdowns of VDAC1 in non-small cell lung cancer cells, and stimulated the extrinsic apoptotic pathway principally by incubating cells with the death ligand TRAIL. We used in-vitro apoptotic and cell viability assays, as well as western blot for markers of apoptosis, to demonstrate that TRAIL-induced toxicity is VDAC1 dependant. Confocal microscopy and mitochondrial fractionation were used to determine the importance of mitochondria for caspase-8 activation.
Here we show that either stable or transient knockdown of VDAC1 is sufficient to antagonize TRAIL mediated apoptosis in non-small cell lung cancer (NSCLC) cells. Specifically, VDAC1 is required for processing of procaspase-8 to its fully active p18 form at the mitochondria. Loss of VDAC1 does not alter mitochondrial sensitivity to exogenous caspase-8-cleaved BID induced mitochondrial depolarization, even though VDAC1 expression is essential for TRAIL dependent activation of the intrinsic apoptosis pathway. Furthermore, expression of exogenous VDAC1 restores the apoptotic response to TRAIL in cells in which endogenous VDAC1 has been selectively silenced.
Expression of VDAC1 is required for full processing and activation of caspase-8 and supports a role for mitochondria in regulating apoptosis signaling via the death receptor pathway.

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Available from: Ian Paul, Oct 01, 2015
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    • "VDAC plays a major role in mitochondria mediated apoptosis [3] [6] [16] [17]. Several anti-apoptotic and pro-apoptotic proteins as well as chemicals are known to target VDAC [18] [19] [20]. Intra-mitochondrial calcium overload mediated by VDAC, triggers the formation of permeability transition pore (PTP). "
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    • "Voltage-dependent anion-selective channel protein 1 (VDAC) is a mitochondrial outer membrane protein that regulates ATP/ADP exchange and respiratory control [47]. VDAC has been shown to be proapoptotic by regulation of Bak and Bax [48] as well as activation of caspase-8 to induce extrinsic apoptosis pathway [49]. Thus, we believe that up-regulation of VDAC by Phyllanthus extracts was able to initiate apoptotic cell death in PC-3 cells (Table 2, Group IV). "
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    • "et al. 2008). In intracellular organelles, they modulate the concentration of ions and play important roles in physiological events such as the voltage-dependent anion channel (VDAC) in apoptosis (Chacko et al. 2010 "
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