Primary colorectal tumors fail to express the proapoptotic mediator PTAG and its reexpression augments drug-induced apoptosis.
Genes implicated in tumor evolution and progression, including those in apoptotic pathways, are associated with methylation-associated gene silencing in different tumor types. By exploiting differential methylation we recently isolated a novel pituitary tumor derived apoptosis gene (PTAG) that augments drug-induced apoptosis. The importance of PTAG was determined in other tumor types, and these studies show that the majority of primary colorectal tumors fail to express the PTAG gene, indicating an important role for PTAG in colorectal tumorigenesis. The effects of expression of PTAG were examined through stable transfection of the colorectal cell lines HCT116 and SW480. Expression of PTAG, per se, had no discernible effects on cell viability or cell kinetics. In contrast to these findings, in cells subject to drug challenges that engaged either a death-receptor mediated or mitochondrial pathway, all of the experiments indicated a role for PTAG in the intrinsic pathway of apoptosis. Loss of PTAG therefore contributes to a blunted apoptotic response and is likely to predispose cells toward malignant transformation and resistance to chemotherapeutic interventions.
Bahar
Adil
A
Institute of Science and Technology in Medicine, School of Medicine, Keele University, Stoke on Trent, Staffordshire ST4 7QB, UK.
Whitby
Philip
P
Holley
Sarah
S
Hoban
Paul R
PR
Elder
James B
JB
Deakin
Mark
M
Hall
Christine
C
Clayton
Richard N
RN
Williams
Gwyn T
GT
Farrell
William E
WE
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*
D051017:Apoptosis Regulatory Proteins; D009363:Neoplasm Proteins; C496066:RHBDD3 protein, human