Resveratrol Induces p53-independent, X-linked Inhibitor of Apoptosis Protein (XIAP)-mediated Bax Protein Oligomerization on Mitochondria to Initiate Cytochrome c Release and Caspase Activation

Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 06/2011; 286(33):28749-60. DOI: 10.1074/jbc.M110.202440
Source: PubMed


Resveratrol, a naturally occurring phytoalexin, is known to induce apoptosis in multiple cancer cell types, but the underlying molecular mechanisms remain unclear. Here, we show that resveratrol induced p53-independent, X-linked inhibitor of apoptosis protein (XIAP)-mediated translocation of Bax to mitochondria where it underwent oligomerization to initiate apoptosis. Resveratrol treatment promoted interaction between Bax and XIAP in the cytosol and on mitochondria, suggesting that XIAP plays a critical role in the activation and translocation of Bax to mitochondria. This process did not involve p53 but required accumulation of Bim and t-Bid on mitochondria. Bax primarily underwent homo-oligomerization on mitochondria and played a major role in release of cytochrome c to the cytosol. Bak, another key protein that regulates the mitochondrial membrane permeabilization, did not interact with p53 but continued to associate with Bcl-xL. Thus, the proapoptotic function of Bak remained suppressed during resveratrol-induced apoptosis. Caspase-9 silencing inhibited resveratrol-induced caspase activation, whereas caspase-8 knockdown did not affect caspase activity, suggesting that resveratrol induces caspase-9-dependent apoptosis. Together, our findings characterize the molecular mechanisms of resveratrol-induced caspase activation and subsequent apoptosis in cancer cells.

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    • "Bax is a p53 primary-response gene and is involved in the apoptotic induction regulated by p53. p53 directly activates the proapoptotic protein bax to permeabilize mitochondria and engage the apoptotic pathway (15,16). The anti-apoptotic protein bcl-2, which prevents disruption of the mitochondrial physiology, is a response gene of p53 and involved in p53-regulated apoptosis (17). "
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    • "Resveratrol is one such factor. Resveratrol induces Bax oligomerization and activation within the cytosol in a process mediated by the X-linked inhibitor of apoptosis protein (Gogada et al., 2011). Activated Bax thereafter translocates to the mitochondria to initiate cytochrome c release, caspase activation and resulting apoptosis . "
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    • "This is in agreement with previous studies on osteosarcoma cells (Bykov et al, 2005). Interestingly, p53-independent upregulation of Puma and Bax has been shown previously in other cancer types (Jeffers et al, 2003; Gogada et al, 2011). Along with increased pro-apoptotic Puma and Bax, MIRA-1 decreased anti-apoptotic proteins Mcl-1 and c-Myc in MM cells. "
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