title: Calmodulin antagonists promote TRA-8 therapy of resistant pancreatic cancer.
abstract: 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.
authors: Department of Pathology, University of Alabama at Birmingham, Alabama 35294, Birmingham, USA.
authors: Kaiyu
authors: K
authors: Yuan
authors: Department of Pathology, University of Alabama at Birmingham, Alabama 35294, Birmingham, USA.
authors: Sun
authors: S
authors: Yong
authors: Department of Pathology, University of Alabama at Birmingham, Alabama 35294, Birmingham, USA.
authors: Fei
authors: F
authors: Xu
authors: Department of Medicine, University of Alabama at Birmingham, Alabama 35294, Birmingham, USA.
authors: Tong
authors: T
authors: Zhou
authors: Department of Pathology, University of Alabama at Birmingham, Alabama 35294, Birmingham, USA.|Birmingham Veterans Affairs Medical Center, Alabama 35294, Birmingham, USA.
authors: Jay M
authors: JM
authors: McDonald
authors: Department of Pathology, University of Alabama at Birmingham, Alabama 35294, Birmingham, USA.|Birmingham Veterans Affairs Medical Center, Alabama 35294, Birmingham, USA.
authors: Yabing
authors: Y
authors: Chen
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D002147:Calmodulin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D045744:Cell Line, Tumor; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004789:Enzyme Activation; D006801:Humans; D008297:Male; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016329:Sp1 Transcription Factor / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection; D014268:Trifluoperazine / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D002147:Calmodulin; D061945:Caspase Inhibitors; D053418:Death Domain Receptor Signaling Adaptor Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; C572208:TRA-8 monoclonal antibody; D013629:Tamoxifen; D014268:Trifluoperazine; D019061:src-Family Kinases; C505530:CASP8 protein, human; D053181:Caspase 8
keywords: apoptosis; calmodulin antagonists; death receptor 5; pancreatic cancer; resistance