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J. Biol. Chem., Vol. 282, Issue 22, 15954-15964, June 1, 2007

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Curcumin Prevents Tumor-induced T Cell Apoptosis through Stat-5a-mediated Bcl-2 Induction^*

From the Bose Institute, P-1/12 Calcutta Improvement Trust Scheme VII M, Kolkata 700 054, India

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 chain (c) expression in T cells by tumor-secreted prostaglandin E₂. 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-5a₇₁₃ 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.

Received for publication, August 25, 2006 , and in revised form, March 13, 2007.

^* This work was supported by research grants from the Department of Science and Technology and the Council for Scientific and Industrial Research, Government of India. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 91-33-2355-9416/2355-9219/2355-9544; Fax: +91-33-2355–3886; E-mail: gauri{at}bic.boseinst.ernet.in.

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