Abstract
TRAIL is a promising therapeutic agent for human malignancies. TRAIL often requires mitochondrial dysfunction, referred to as the Type II death receptor pathway, to promote cytotoxicity. However, numerous malignant cells are TRAIL resistant due to inhibition of this mitochondrial pathway. Using cholangiocarcinoma cells as a model of TRAIL resistance, we found that Hedgehog signaling blockade sensitized these cancer cells to TRAIL cytotoxicity independent of mitochondrial dysfunction, referred to as Type I death receptor signaling. This switch in TRAIL requirement from Type II to Type I death receptor signaling was demonstrated by the lack of functional dependence on Bid/Bim and Bax/Bak, proapoptotic components of the mitochondrial pathway. Hedgehog signaling modulated expression of X-linked inhibitor of apoptosis (XIAP), which serves to repress the Type I death receptor pathway. siRNA targeted knockdown of XIAP mimics sensitization to mitochondria-independent TRAIL killing achieved by Hedgehog inhibition. Regulation of XIAP expression by Hedgehog signaling is mediated by the glioma-associated oncogene 2 (GLI2), a downstream transcription factor of Hedgehog. In conclusion, these data provide additional mechanisms modulating cell death by TRAIL and suggest Hedgehog inhibition as a therapeutic approach for TRAIL-resistant neoplasms.
Highlights
Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), a potent death ligand that preferentially induces apoptosis in transformed cells, initiates signaling cascades by ligating two death receptors, DR4 (TNFRSF10A, referred to as TRAIL receptor 1) and DR5 (TNFRSF10B, referred to as TRAIL receptor 2/KILLER/TRICK-2) [1]
The results demonstrate that in human cholangiocarcinoma cells, (i) Hedgehog pathway inhibition sensitizes human cholangiocarcinoma cells to TRAIL-mediated apoptosis, in part, by down-regulating X-linked inhibitor of apoptosis (XIAP) protein; (ii) XIAP repression by SMO inhibition occurs at the mRNA level as well, consistent with GLImediated enhancement of XIAP transcription; and (iii) inhibition of Hedgehog promotes TRAIL cytotoxicity independent of Bid, Bim, Bax, and Bak
These data suggest inhibition of Hedgehog signaling modulates TRAIL cytotoxicity in human cholangiocarcinoma cells by regulating XIAP expression and converting TRAIL signaling from Type II to Type I apoptotic signaling
Summary
Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), a potent death ligand that preferentially induces apoptosis in transformed cells, initiates signaling cascades by ligating two death receptors, DR4 (TNFRSF10A, referred to as TRAIL receptor 1) and DR5 (TNFRSF10B, referred to as TRAIL receptor 2/KILLER/TRICK-2) [1]. TRAIL-induced clustering and oligomerization of DR4 and DR5 results in conformational changes of the death domains within their cytoplasmic tails, facilitating recruitment and activation of caspases 8 and 10 within a death inducing signaling complex (DISC) [2,3,4]. If activation of these initiator caspases is sufficiently robust, they directly activate caspase 3, which in turn results in cellular demise by the so-called Type I death receptor pathway of apoptosis [5,6]. TRAIL usually signals through the Type II, mitochondriadependent pathway [11], a pathway which is frequently inhibited in cancers resulting in TRAIL resistance [12,13]
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