Curcumin prevents tumor-induced T cell apoptosis through Stat-5a-mediated Bcl-2 induction
Curcumin prevents tumor-induced T cell apoptosis through Stat-5a-mediated Bcl-2 induction
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DOI：
10.1074/jbc.m608189200
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发表时间：
2007-06-01
影响因子：
4.8
通讯作者：
Sa, Gaurisankar
中科院分区：
文献类型：
--
作者：
Bhattacharyya, Sankar;Mandal, Debaprasad;Sa, Gaurisankar
晚期癌症患者在免疫能力方面表现出多方面的缺陷，这可能导致对感染和疾病进展的易感性增加。我们之前证明了姜黄素抑制肿瘤生长并防止荷瘤宿主的免疫细胞死亡。在这里，我们报告了肿瘤诱导的免疫耗竭涉及胸腺CD 4（+）/CD 8（+）单/双阳性细胞的凋亡以及循环CD 4（+）/CD 8（+）T细胞的丢失。给荷瘤动物施用姜黄素导致祖细胞、效应细胞和循环T细胞的恢复。事实上，肿瘤负荷降低了T细胞中促增殖蛋白Bcl-2的表达水平，同时增加了促凋亡蛋白Bax。姜黄素下调Bax水平，同时增加Bcl-2在这些细胞中的表达，从而保护免疫细胞免受肿瘤诱导的凋亡。对上游机制的研究揭示了肿瘤分泌的前列腺素E-2对T细胞中常见细胞因子受体γ链（γ c）表达的下调。结果，在T细胞中，Jak-3和Stat-5a磷酸化以及较小程度的Stat-5 b磷酸化也降低。这些现象都可以被姜黄素逆转，表明这种植物化学物质恢复了肿瘤携带者T细胞中的姜黄素依赖性Jak-3/Stat-5a信号通路。过表达的Stat-5a/组成型活性的Stat-5a 1 *6而不是Stat-5 b可以有效地提高Bcl-2水平并保护T细胞免受肿瘤诱导的死亡，而C端截短的Stat-5a（713）过表达则不能做到这一点，表明Stat-5a信号传导在T细胞存活中的重要性。因此，这些结果提高了在成功的抗癌治疗方案中包含姜黄素的可能性。
Patients with advanced cancer exhibit multifaceted defects in their immune capacity, which are likely to contribute to an increased susceptibility to infections and disease progression. We demonstrated earlier that curcumin inhibits tumor growth and prevents immune cell death in tumor-bearing hosts. Here we report that tumor-induced immunodepletion involves apoptosis of thymic CD4(+)/CD8(+) single/double positive cells as well as loss of circulating CD4(+)/CD8(+) T cells. Administration of curcumin to tumor-bearing animals resulted in restoration of progenitor, effecter, and circulating T cells. In fact, tumor burden decreased the expression level of the pro-proliferative protein Bcl-2 while increasing the pro-apoptotic protein Bax in T cells. Curcumin down-regulated the Bax level while augmenting Bcl-2 expression in these cells, thereby protecting the immunocytes from tumor-induced apoptosis. A search for the upstream mechanism revealed down-regulation of the common cytokine receptor gamma chain (gamma c) expression in T cells by tumor-secreted prostaglandin E-2. As a result, Jak-3 and Stat-5a phosphorylation and to a lesser extent Stat-5b phosphorylation were also decreased in T cells. These entire phenomena could be reverted back by curcumin, indicating that this phytochemical restored the cytokine-dependent Jak-3/Stat-5a signaling pathway in T cells of tumor bearers. Overexpressed Stat-5a/constitutively active Stat-5a1*6 but not Stat-5b could efficiently elevate Bcl-2 levels and protect T cells from tumor-induced death, whereas C-terminal truncated Stat-5a(713) overexpression failed to do so, indicating the importance of Stat-5a signaling in T cell survival. Thus, these results raise the possibility of inclusion of curcumin in successful therapeutic regimens against cancer.