Journal
CANCER LETTERS
Volume 482, Issue -, Pages 19-32Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2020.02.041
Keywords
Apoptosis; BCL-2 proteins; A-1331852; S63845; Rhabdomyosarcoma
Categories
Funding
- Deutsche Krebshilfe
- BMBF
- Medical Faculty, Goethe-University Frankfurt
Ask authors/readers for more resources
With the development of potent and selective inhibitors of MCL-1 (S63845) and BCL-X-L (A-1331852) novel cancer treatment options have emerged. BCL-2 family proteins are important regulators of apoptosis in pediatric solid tumors. In the current study, we discover that rhabdomyosarcoma, Ewing sarcoma, osteosarcoma and neuroblastoma cell lines are co-dependent on BCL-X-L and MCL-1 for survival. A-1331852/S63845 co-treatment, but not combinations of either inhibitor with ABT-199, synergistically induces rapid intrinsic apoptosis in vitro and demonstrates efficiency in an in vivo embryonic chicken model of rhabdomyosarcoma. Interestingly, A-1331852/S63845-induced apoptosis is BAX/BAK-dependent and mediated by displacement of BAK from BCL-X-L and MCL-1, respectively. Moreover, BAK interacts with BAX to build a pore-forming complex in the outer mitochondrial membrane, leading to loss of mitochondrial outer membrane potential and caspase activation. Furthermore, in RD cells A-1331852/S63845 co-treatment disrupts BIM and NOXA in their interactions with BCL-X-L and MCL-1, respectively, thereby contributing to apoptosis. Altogether, this study is the first to demonstrate the potency of A-1331852/S63845 in pediatric solid tumor cells and to describe the molecular mechanisms of A-1331852/S63845 co-treatment underlining the potential of BCL-X-L and MCL-1 inhibition as treatment regime.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available