Targeting constitutive and interleukin-6-inducible signal transducers and activators of transcription 3 pathway in head and neck squamous cell carcinoma cells by curcumin (diferuloylmethane)
Targeting constitutive and interleukin-6-inducible signal transducers and activators of transcription 3 pathway in head and neck squamous cell carcinoma cells by curcumin (diferuloylmethane)
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DOI：
10.1002/ijc.21967
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发表时间：
2006-09-15
影响因子：
6.4
通讯作者：
Aggarwal, Bharat B.
中科院分区：
文献类型：
--
作者：
Chakravarti, Nitin;Myers, Jeffrey N.;Aggarwal, Bharat B.
大量研究表明，白细胞介素-6（IL-6）通过磷酸化细胞信号转导蛋白和转录激活因子-3（STAT 3）促进肿瘤细胞的存活和增殖。头颈部鳞状细胞癌（HNSCC）中STAT 3的组成性激活及其在肿瘤增殖中的作用已被证实。因此，可以抑制STAT 3活化的药剂具有治疗HNSCC的潜力。在本报告中，我们证明了大多数HNSCC细胞系具有组成型活性STAT 3，并且姜黄素（二阿魏酰甲烷），一种人体内安全的药物，以剂量和时间依赖性方式抑制STAT 3磷酸化。姜黄素也能抑制STAT 3的核转位。姜黄素对STAT 3激活的抑制是可逆的，尽管在去除姜黄素后甚至24小时，仅发生部分逆转。除了抑制组成型表达外，姜黄素还消除了HNSCC细胞中IL-6诱导的STAT 3活化。当与AG 490（一种充分表征的JAK 2抑制剂）相比时，姜黄素是STAT 3磷酸化的更快速（30分钟对4小时）和更有效（25 μ M对100 μ M）的抑制剂。姜黄素也是比AG 490更有效的HNSCC细胞增殖抑制剂。总的来说，我们的研究结果表明，姜黄素是一种有效的抑制剂组成和IL-6诱导的STAT 3磷酸化。这种机制可能至少部分地负责姜黄素抑制HNSCC细胞增殖的能力。(c)2006 Wiley-Liss，Inc.
Numerous reports suggest that interleukin-6 (IL-6) promotes survival and proliferation of tumor cells through the phosphorylation of a cell-signaling protein, signal-transducer-and-activator-of-transcription-3 (STAT3). Constitutive activation of STAT3 in head and neck squamous cell carcinoma (HNSCC) and its role in proliferation of this tumor has been demonstrated. Thus, agents that can suppress STAT3 activation have potential for the treatment of HNSCC. In the present report, we demonstrate that most HNSCC cell lines had constitutively active STAT3 and that curcumin (diferuloylmethane), a pharmacologically safe agent in humans, inhibited STAT3 phosphorylation in a dose- and time-dependent manner. Nuclear translocation of STAT3 was also inhibited by curcumin. The inhibition of STAT3 activation by curcumin was reversible, although even 24 hr after curcumin removal, only partial reversal occurred. Besides inhibiting constitutive expression, curcumin also abrogated the IL-6-induced activation of STAT3 in HNSCC cells. When compared with AG490, a well-characterized JAK2 inhibitor, curcumin was more rapid (30 min vs. 4 hr) and more potent (25 mu M vs. 100 mu M) inhibitor of STAT3 phosphorylation. Curcumin was also a more potent inhibitor of HNSCC cell proliferation than AG490. Overall, our results demonstrated that curcumin is a potent inhibitor of constitutive and IL-6-induced STAT3 phosphorylation. This mechanism may be at least partially responsible for curcumin's ability to suppress proliferation of HNSCC cells. (c) 2006 Wiley-Liss, Inc.