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Originally published In Press as doi:10.1074/jbc.M308062200 on November 25, 2003
J. Biol. Chem., Vol. 279, Issue 7, 6065-6076, February 13, 2004
Evidence That Receptor Activator of Nuclear Factor (NF)- B Ligand Can Suppress Cell Proliferation and Induce Apoptosis through Activation of a NF-B-independent and TRAF6-dependent Mechanism*
Alok C. Bharti,
Yasunari Takada,
Shishir Shishodia, and
Bharat B. Aggarwal
From the
Cytokine Research Section, Department of Bioimmunotherapy, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030
The receptor activator of NF- B ligand (RANKL), a recently identified member of the tumor necrosis factor (TNF) superfamily, has been shown to induce osteoclastogenesis and dendritic cell survival. Most members of the TNF superfamily suppress cell proliferation and induce apoptosis, but whether RANKL does so is not known. We demonstrate that treatment of monocyte RAW 264.7 cells with RANKL induces dose-dependent growth inhibition (IC50 = 10 ng/ml) as determined by dye uptake and [3H]thymidine incorporation methods. Suppression of RANKL-induced NF-B activation by dominant-negative IB or by the NEMO-peptide had no effect on RANKL-induced cell growth inhibition. Inhibition of RANKL-induced JNK activation, however, abolished the RANKL-induced apoptosis. Suppression of interaction of RANK with TRAF6 by TRAF6-binding peptide abrogated the anti-proliferative effects of RANKL, suggesting the critical role of TRAF6. Flow cytometric analysis of cells treated with RANKL showed accumulation of cells in G0/G1 phase of the cell cycle, and this accumulation correlated with a decline in the levels of cyclin D1, cyclin D3, and cyclin E and an increase in cyclin-dependent kinase inhibitor p27 (Kip). Flow cytometric analysis showed the presence of annexin V-positive cells in cultures treated with RANKL. RANKL-induced apoptosis was further confirmed using calcein AM/ethidium homodimer-1 dye and cleavage of poly(ADP-ribose) polymerase (PARP), procaspase 3, and procaspase 9; benzyloxycarbonyl-VAD, the pancaspase inhibitor, suppressed the PARP cleavage. Thus, overall, our studies indicate that RANKL can inhibit cell proliferation and induce apoptosis through a TRAF-6-dependent but NF-B-independent mechanism.
Received for publication, July 24, 2003
, and in revised form, November 19, 2003.
* This work was supported by the Clayton Foundation for Research (to B. B. A.), Department of Defense, U. S. Army Breast Cancer Research Program Grant BC010610 (to B. B. A.), PO1 Grant CA91844 on lung chemoprevention from the National Institutes of Health (to B. B. A.), and a P50 Head and Neck Specialized Programs of Research Excellence grant from the National Institutes of Health (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.
 To whom correspondence should be addressed: Cytokine Research Section, Dept. of Bioimmunotherapy, Unit 143, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Tel.: 713-792-3503 (ext. 6459); Fax: 713-794-1613; E-mail: aggarwal{at}mdanderson.org.
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Copyright © 2004 by the American Society for Biochemistry and Molecular Biology.
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