Abstract
The proteasome inhibitor Bortezomib has been identified as a potent enhancer of TRAIL-induced apoptosis in several human cancers. However, the identification of the underlying molecular mechanisms of this synergistic cell death induction has been ongoing over the last years. A recent study identifies a new mechanism of action for the synergism of TRAIL and Bortezomib.
Highlights
A recent study identifies a novel mechanism of action that underlies the synergistic cooperation of TRAIL and Bortezomib by demonstrating for the first time that Bortezomib enhances the stability of TRAILderived tBid, the cleaved form of Bid [8]
It is interesting to note that Noxa turned out in the current study to determine only the kinetic of apoptosis induction, while it became dispensable for apoptosis upon prolonged exposure to Bortezomib and TRAIL [8]
Noxa has been shown to be a critical mediator of apoptosis upon monotherapy with Bortezomib [17,18,19], pointing to differences in the role of Noxa between single agent and combination therapy with Bortezomib
Summary
A recent study identifies a novel mechanism of action that underlies the synergistic cooperation of TRAIL and Bortezomib by demonstrating for the first time that Bortezomib enhances the stability of TRAILderived tBid, the cleaved form of Bid [8]. Bim and/or Bik [11, 12], to block the degradation of Bax [13] or to promote the release of Smac from the mitochondria into the cytosol [14]. Bortezomib alone or in combination with TRAIL has been shown to downregulate or cleave anti-apoptotic Bcl-2 proteins such as Bcl-2, Bcl-XL or Mcl-1 [15, 16].
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