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.
Galectin-3 (GAL3), a beta-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.
Mazurek
Nachman
N
Department of Gastrointestinal Medicine and Nutrition, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Sun
Yun Jie
YJ
Liu
Kai-Feng
KF
Gilcrease
Michael Z
MZ
Schober
Wendy
W
Nangia-Makker
Pratima
P
Raz
Avraham
A
Bresalier
Robert S
RS
D017209:Apoptosis; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism*; D002879:Chromosomes, Human, Pair 10; D045304:Cytochromes c / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D037502:Galectin 3 / Q000378:metabolism* / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*
D004791:Enzyme Inhibitors; D037502:Galectin 3; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D045304:Cytochromes c; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human