Tissue transglutaminase induces the release of apoptosis inducing factor and results in apoptotic death of pancreatic cancer cells.
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignant disease with poor long-term survival rates. Major reason for poor disease outcome is the profound intrinsic resistance of PDAC cells to currently available treatment regimens. We recently found that a great majority of PDAC tumors and tumor cell lines express high basal level of tissue transglutaminase (TG2), a multifunctional protein implicated in apoptosis, cell attachment, cell survival, and cell motility functions. Based on these observations, we hypothesized that activation of endogenous TG2 can induce spontaneous apoptosis in PDAC cells. The results obtained suggested that activation of endogenous TG2 by calcium ionophore A23187 induced rapid and spontaneous apoptosis in PDAC cells. TG2-induced apoptosis was associated with release of apoptosis-inducing factor (AIF). The release of AIF from mitochondria led to its translocation to the nucleus and subsequent apoptosis of PDAC cells in caspase-independent manner. In conclusion, our results provide first evidence that TG2 can induce apoptosis in PDAC cells in an AIF-dependent and caspase-independent manner.
Fok
Jansina Y
JY
Department of Experimental Therapeutics, Unit 362, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Mehta
Kapil
K
D017209:Apoptosis; D051033:Apoptosis Inducing Factor / Q000378:metabolism*; D000001:Calcimycin / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000473:pathology*; D016923:Cell Death; D002454:Cell Differentiation; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D018450:Disease Progression; D019204:GTP-Binding Proteins; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007476:Ionophores / Q000494:pharmacology; D008954:Models, Biological; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology*; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor; D015220:Calcium Channels; D007476:Ionophores; D003841:Deoxycytidine; D000001:Calcimycin; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; D000093542:Gemcitabine