Authors: | Zhang, H; Lin, Y; Manas, A.; Zhao, Y.; Denning, M. F.; Ma, L.; Xiang, J. |
Article Title: | Baxdelta2 Promotes Apoptosis through Caspase-8 Activation in Microsatellite Unstable Colon Cancer |
Abstract: | Loss of apoptotic Bax due to microsatellite mutation contributes to tumor development and chemoresistance. Recently a Bax microsatellite mutation was uncovered in combination with a specific alternative splicing event that could generate a unique Bax isoform (Baxdelta2) in otherwise Bax-negative cells. Like the prototype Baxalpha, Baxdelta2 is a potent pro-apoptotic molecule. However, the pro-apoptotic mechanism and therapeutic implication of Baxdelta2 remain elusive. Here, the isolation and analysis of isogenic sub-cell lines are described that represent different Bax microsatellite statuses from colorectal cancer. Colon cancer cells harboring Bax microsatellite G7/G7 alleles are capable of producing low levels of endogenous Baxdelta2 transcripts and proteins. Interestingly, Baxdelta2-positive cells are selectively sensitive to a subgroup of chemotherapeutics compared with Baxdelta2-negative cells. Unlike other Bax isoforms, Baxdelta2 recruits caspase-8 into the proximity for activation, and the latter, in turn, activates caspase-3 and apoptosis independent of the mitochondrial pathway. These data suggest that the expression of Baxdelta2 may provide alternative apoptotic and chemotherapeutic advantages for Bax-negative tumors. Implications: Bax-negative colorectal tumors expressing a Bax isoform are sensitive to selective chemotherapeutics. |
Journal Title: | Molecular cancer research : MCR |
Volume: | 12 |
Issue: | 9 |
ISSN: | 1557-3125; 1541-7786 |
Publisher: | Unknown |
Date Published: | 2014 |
Start Page: | 1225 |
End Page: | 1232 |
Language: | ENG |
DOI/URL: |
molcanres.0162.2014 |
Notes: | CI: (c)2014; GR: R01 CA128114/CA/NCI NIH HHS/United States; JID: 101150042; 0 (Protein Isoforms); 0 (bcl-2-Associated X Protein); EC 3.4.22.- (Caspase 3); EC 3.4.22.- (Caspase 8); 2014/05/19 [aheadofprint]; ppublish |