Calmodulin antagonists promote TRA-8 therapy of resistant pancreatic cancer
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Kaiyu Yuan1, Sun Yong1, Fei Xu1, Tong Zhou2, Jay M McDonald1,3, Yabing Chen1,3
1Department of Pathology, University of Alabama at Birmingham, Alabama 35294, Birmingham, USA
2Department of Medicine, University of Alabama at Birmingham, Alabama 35294, Birmingham, USA
3Birmingham Veterans Affairs Medical Center, Alabama 35294, Birmingham, USA
Yabing Chen, e-mail: [email protected]
Keywords: death receptor 5, apoptosis, resistance, calmodulin antagonists, pancreatic cancer
Received: April 06, 2015 Accepted: June 30, 2015 Published: July 11, 2015
Pancreatic cancer is highly malignant with limited therapy and a poor prognosis. TRAIL-activating therapy has been promising, however, clinical trials have shown resistance and limited responses of pancreatic cancers. We investigated the effects of calmodulin(CaM) antagonists, trifluoperazine(TFP) and tamoxifen(TMX), on TRA-8-induced apoptosis and tumorigenesis of TRA-8-resistant pancreatic cancer cells, and underlying mechanisms. TFP or TMX alone did not induce apoptosis of resistant PANC-1 cells, while they dose-dependently enhanced TRA-8-induced apoptosis. TMX treatment enhanced efficacy of TRA-8 therapy on tumorigenesis in vivo. Analysis of TRA-8-induced death-inducing-signaling-complex (DISC) identified recruitment of survival signals, CaM/Src, into DR5-associated DISC, which was inhibited by TMX/TFP. In contrast, TMX/TFP increased TRA-8-induced DISC recruitment/activation of caspase-8. Consistently, caspase-8 inhibition blocked the effects of TFP/TMX on TRA-8-induced apoptosis. Moreover, TFP/TMX induced DR5 expression. With a series of deletion/point mutants, we identified CaM antagonist-responsive region in the putative Sp1-binding domain between -295 to -300 base pairs of DR5 gene. Altogether, we have demonstrated that CaM antagonists enhance TRA-8-induced apoptosis of TRA-8-resistant pancreatic cancer cells by increasing DR5 expression and enhancing recruitment of apoptotic signal while decreasing survival signals in DR5-associated DISC. Our studies support the use of these readily available CaM antagonists combined with TRAIL-activating agents for pancreatic cancer therapy.
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