Calmodulin antagonists promote TRA-8 therapy of resistant pancreatic cancer.
Calmodulin antagonists promote TRA-8 therapy of resistant pancreatic cancer.
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DOI：
10.18632/oncotarget.4490
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发表时间：
2015-09-22
期刊：
影响因子：
--
通讯作者：
Chen Y
中科院分区：
文献类型：
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作者：
Yuan K;Yong S;Xu F;Zhou T;McDonald JM;Chen Y
胰腺癌恶性程度高，治疗有限，预后较差。 TRAIL 激活疗法一直很有前景，但临床试验显示胰腺癌存在耐药性且反应有限。我们研究了钙调蛋白（CaM）拮抗剂三氟拉嗪（TFP）和他莫昔芬（TMX）对TRA-8诱导的TRA-8耐药胰腺癌细胞凋亡和肿瘤发生的影响及其潜在机制。单独使用 TFP 或 TMX 不会诱导耐药 PANC-1 细胞凋亡，但它们会剂量依赖性地增强 TRA-8 诱导的细胞凋亡。 TMX 治疗增强了 TRA-8 疗法对体内肿瘤发生的功效。对 TRA-8 诱导的死亡诱导信号复合物 (DISC) 的分析发现，生存信号 CaM/Src 募集到 DR5 相关的 DISC 中，该信号被 TMX/TFP 抑制。相反，TMX/TFP 增加 TRA-8 诱导的 DISC 募集/激活 caspase-8。一致地，caspase-8 抑制阻断了 TFP/TMX 对 TRA-8 诱导的细胞凋亡的影响。此外，TFP/TMX 诱导 DR5 表达。通过一系列缺失/点突变，我们在 DR5 基因的 -295 至 -300 个碱基对之间的假定 Sp1 结合域中鉴定了 CaM 拮抗剂响应区域。总而言之，我们已经证明，CaM 拮抗剂通过增加 DR5 表达和增强凋亡信号的募集，同时减少 DR5 相关 DISC 中的生存信号，增强 TRA-8 诱导的 TRA-8 耐药胰腺癌细胞凋亡。我们的研究支持使用这些现成的 CaM 拮抗剂与 TRAIL 激活剂联合用于胰腺癌治疗。
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.