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: Kaiyu Yuan, Sun Yong, Fei Xu, Tong Zhou, Jay M McDonald, Yabing Chen
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 28 Pg. 25308-19 (Sep 22 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26320171 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents
• Calmodulin
• Caspase Inhibitors
• Death Domain Receptor Signaling Adaptor Proteins
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• Sp1 Transcription Factor
• SP1 protein, human
• TRA-8 monoclonal antibody
• Tamoxifen
• Trifluoperazine
• src-Family Kinases
• CASP8 protein, human
• Caspase 8

Topics

• Animals
• Antibodies, Monoclonal (pharmacology)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Binding Sites
• Calmodulin (antagonists & inhibitors, metabolism)
• Caspase 8 (metabolism)
• Caspase Inhibitors (pharmacology)
• Cell Line, Tumor
• Death Domain Receptor Signaling Adaptor Proteins (metabolism)
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm (drug effects)
• Enzyme Activation
• Humans
• Male
• Mice, Nude
• Pancreatic Neoplasms (drug therapy, genetics, metabolism, pathology)
• Promoter Regions, Genetic
• Protein Binding
• Receptors, TNF-Related Apoptosis-Inducing Ligand (genetics, metabolism)
• Signal Transduction (drug effects)
• Sp1 Transcription Factor (metabolism)
• Tamoxifen (pharmacology)
• Time Factors
• Transfection
• Trifluoperazine (pharmacology)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays
• src-Family Kinases (metabolism)