Abstract
Resistance to apoptosis is a hallmark of pancreatic cancer, a leading cause of cancer deaths. Therefore, novel strategies are required to target apoptosis resistance. Here, we report that the combination of X-linked inhibitor of apoptosis (XIAP) inhibition and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an effective approach to trigger apoptosis despite Bcl-2 overexpression and to suppress pancreatic cancer growth in vitro and in vivo. Knockdown of XIAP by RNA interference cooperates with TRAIL to induce caspase activation, loss of mitochondrial membrane potential, cytochrome c release, and apoptosis in pancreatic carcinoma cells. Loss of mitochondrial membrane potential and cytochrome c release are extensively inhibited by a broad range or caspase-3 selective caspase inhibitor and by RNAi-mediated silencing of caspase-3, indicating that XIAP inhibition enhances TRAIL-induced mitochondrial damage in a caspase-3-dependent manner. XIAP inhibition combined with TRAIL even breaks Bcl-2-imposed resistance by converting type II cells that depend on the mitochondrial contribution to the death receptor pathway to type I cells in which TRAIL-induced activation of caspase-3 and caspase-9 and apoptosis proceeds irrespective of high Bcl-2 levels. Most importantly, XIAP inhibition potentiates TRAIL-induced antitumor activity in two preclinical models of pancreatic cancer in vivo. In the chicken chorioallantoic membrane model, XIAP inhibition significantly enhances TRAIL-mediated apoptosis and suppression of tumor growth. In a tumor regression model in xenograft-bearing mice, XIAP inhibition acts in concert with TRAIL to cause even regression of established pancreatic carcinoma. Thus, this combination of XIAP inhibition plus TRAIL is a promising strategy to overcome apoptosis resistance of pancreatic cancer that warrants further investigation.
Highlights
Despite intensive protocols, treatment resistance of pancreatic cancer considerably contributes to the poor prognosis of this disease [1, 2]
To antagonize X-linked inhibitor of apoptosis (XIAP) in pancreatic cancer, we generated clones of PancTu1 and PaTuII pancreatic carcinoma cells in which XIAP was substantially down-regulated by retroviral short-hairpin RNA vectors (Fig. 1A)
Knockdown of survivin significantly increased apoptosis without the addition of tumor necrosis factor–related apoptosisinducing ligand (TRAIL) and acted in concert with TRAIL to induce apoptosis (Supplementary Fig. S2). These findings show that inhibition of XIAP or survivin sensitizes pancreatic carcinoma cells to TRAIL-induced apoptosis
Summary
Treatment resistance of pancreatic cancer considerably contributes to the poor prognosis of this disease [1, 2]. Effector caspases are activated upon the release of apoptogenic factors such as cytochrome c or second mitochondriaderived activator of caspase (Smac)/direct inhibitor of apoptosis protein (IAP) binding protein with low PI (DIABLO) from mitochondria into the cytosol [7]. The mitochondrial contribution to death receptor signaling is of special relevance in type II cells, for example pancreatic carcinoma, which rely on the apoptotic function of mitochondria for full activation of caspase-3 and apoptosis [8,9,10]. In type I cells, caspase-8 is activated upon death receptor ligation at the death-inducing signaling complex (DISC) in quantities sufficient to directly activate caspase-3 [8]. Blocking the mitochondrial pathway, e.g., by overexpression of Bcl-2, inhibits death receptor-induced apoptosis in type II but not in type I cells [8]
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