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J. Biol. Chem., Vol. 281, Issue 23, 16034-16042, June 9, 2006

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PUMA Dissociates Bax and Bcl-X_L to Induce Apoptosis in Colon Cancer Cells^*

Lihua Ming, Peng Wang, Alexander Bank, Jian Yu, and Lin Zhang¹

From the Departments of Pathology and Pharmacology, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213

PUMA is a BH3-only Bcl-2 family protein that plays an essential role in DNA damage-induced apoptosis. PUMA interacts with anti-apoptotic Bcl-2 and Bcl-X_L and is dependent on Bax to induce apoptosis. In this study, we investigated how the interactions of PUMA with the antiapoptotic proteins coordinate with Bax to initiate apoptosis in HCT116 colon cancer cells. We found that Bcl-X_L was most effective among several antiapoptotic proteins in suppressing PUMA-induced apoptosis and PUMA-dependent apoptosis induced by the DNA-damaging agent adriamycin. Mutant Bcl-X_L that cannot interact with Bax was unable to protect cells from PUMA-mediated apoptosis. Knockdown of Bcl-X_L by RNA interference significantly enhanced PUMA-mediated apoptosis in HCT116 cells but not in PUMA-knockout cells. Furthermore, Bax was found to be dissociated preferentially from Bcl-X_L in HCT116 cells but not in the PUMA-knockout cells, in response to PUMA induction and adriamycin treatment. PUMA inhibited the association of Bax and Bcl-X_L in vitro by directly binding to Bcl-X_L through its BH3 domain. Finally, we found that wild-type Bax, but not mutant Bax deficient in either multimerization or mitochondrial localization, was able to restore PUMA-induced apoptosis in the BAX-knockout cells. Together, these results indicate that PUMA initiates apoptosis in part by dissociating Bax and Bcl-X_L, thereby promoting Bax multimerization and mitochondrial translocation.

Received for publication, December 21, 2005 , and in revised form, March 15, 2006.

^* This work was supported by Grant CA106348 from the National Institutes of Health (to L. Z.), grants from the Edward Mallinckrodt Jr. Foundation and the Elsa U. Pardee Foundation (to L. Z.), and grants from the Flight Attendant Medical Research Institute and the Hillman Foundation (to J. Y.). 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 Scholar of the General Motors Cancer Research Foundation and the V Foundation for Cancer Research. To whom correspondence should be addressed: UPCI Research Pavilion, Rm. 2.42d, Hillman Cancer Center, 5117 Centre Ave., University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213. Tel.: 412-623-1009; Fax: 412-623-7778; E-mail: zhanglx{at}upmc.edu.

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