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J. Biol. Chem., Vol. 282, Issue 29, 21337-21348, July 20, 2007

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Phosphorylated Galectin-3 Mediates Tumor Necrosis Factor-related Apoptosis-inducing Ligand Signaling by Regulating Phosphatase and Tensin Homologue Deleted on Chromosome 10 in Human Breast Carcinoma Cells^*

Nachman Mazurek¹, Yun Jie Sun¹, Kai-Feng Liu, Michael Z. Gilcrease, Wendy Schober^¶, Pratima Nangia-Makker^||, Avraham Raz^||, and Robert S. Bresalier²

From the Departments of Gastrointestinal Medicine and Nutrition, Pathology, and ^¶Blood and Marrow Transplantation, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 and the ^||Tumor Progression and Metastasis Program, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201

Galectin-3 (GAL3), a -galactoside-binding lectin, confers chemoresistance to a wide variety of cancer cell types. It may exhibit anti- or pro-apoptotic activity depending on the nature of the stimulus. We report here that introducing phosphorylated galectin-3 (P-GAL3) into GAL3-null, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistant human breast carcinoma cells promotes TRAIL-induced apoptotic cell death by stimulating the phosphorylation/inactivation of the pro-apoptotic molecule Bad resulting in the inhibition of mitochondrial depolarization and the release of cytochrome c. Exposure of the transfectant cells to TRAIL leads to the recruitment of the initiator capase-8 followed by activation of the effector caspase-9, independent of cytochrome c, and subsequently the processing of the executioner caspase-3. P-GAL3 and phosphatase and tensin homologue deleted on chromosome 10 (PTEN) were coordinately expressed, with concomitant dephosphorylation of Akt in TRAIL-sensitive cells. In contrast, overexpression of phospho-mutant GAL3 (incapable of phosphorylation) failed to elicit similar responses. Depletion of PTEN using small interference RNAs reinstated Akt phosphorylation and conferred TRAIL resistance. In addition phosphatidylinositol 3-kinase inhibitors rendered the phospho-mutant GAL3-resistant cells sensitive to TRAIL. These findings suggest a pivotal role for P-GAL3 in promoting TRAIL sensitivity through activation of a nonclassic apoptotic pathway and identify P-GAL3 as a novel regulator of PTEN.

Received for publication, September 12, 2006 , and in revised form, April 6, 2007.

^* This work was supported by NCI, National Institutes of Health Grants CA69480 (to R. S. B.) and CA16672 to the flow cytometry and image analysis core of the M. D. Anderson Cancer Center. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Gastrointestinal Medicine and Nutrition, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit #436, Houston, TX 77030. Tel.: 713-745-4340; Fax: 713-745-9295; E-mail: rbresali{at}mdanderson.org.

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