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J. Biol. Chem., Vol. 281, Issue 33, 23425-23435, August 18, 2006

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Indirubin Enhances Tumor Necrosis Factor-induced Apoptosis through Modulation of Nuclear Factor-B Signaling Pathway^*

Gautam Sethi, Kwang Seok Ahn, Santosh K. Sandur, Xin Lin, Madan M. Chaturvedi¹, and Bharat B. Aggarwal²

From the Cytokine Research Laboratory, Department of Experimental Therapeutics and Molecular and Cellular Oncology, the University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Although indirubin is known to exhibit anti-cancer and anti-inflammatory activities, very little is known about its mechanism of action. In this study, we investigated whether indirubin mediates its effects through interference with the NF-B pathway. As examined by the DNA binding of NF-B, we found that indirubin suppressed tumor necrosis factor (TNF)-induced NF-B activation in a dose- and time-dependent manner. Indirubin also suppressed the NF-B activation induced by various inflammatory agents and carcinogens. Further studies showed that indirubin blocked the phosphorylation and degradation of IB through the inhibition of activation of IB kinase and phosphorylation and nuclear translocation of p65. NF-B reporter activity induced by TNFR1, TNF receptor-associated death domain, TRAF2, TAK1, NF-B-inducing kinase, and IKK was inhibited by indirubin but not that induced by p65 transfection. We also found that indirubin inhibited the expression of NF-B-regulated gene products involved in antiapoptosis (IAP1, IAP2, Bcl-2, Bcl-x_L, and TRAF1), proliferation (cyclin D1 and c-Myc), and invasion (COX-2 and MMP-9). This correlated with enhancement of the apoptosis induced by TNF and the chemotherapeutic agent taxol in human leukemic KBM-5 cells. Indirubin also suppressed cytokine-induced cellular invasion. Overall, our results indicate that anti-cancer and anti-inflammatory activities previously assigned to indirubin may be mediated in part through the suppression of the NF-B activation pathway.

Received for publication, March 21, 2006 , and in revised form, June 12, 2006.

^* This work was supported by a grant from the Clayton Foundation for Research (to B. B. A.), National Institutes of Health PO1 Grant CA91844 (to B. B. A.), and National Institutes of Health SPORE Grant P50CA97007 (to B. B. A.). 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 On leave from the Dept. of Zoology, University of Delhi, Delhi-110007, India.

² Ransom Horne, Jr., Professor of Cancer Research. To whom correspondence should be addressed: Cytokine Research Laboratory, Dept. of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Tel.: 713-792-3503; Fax: 713-794-1613; E-mail: aggarwal{at}mdanderson.org.

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