What does BCL-2 do? From new molecular insights to the clinical implications - PubMed
3 days ago
- #Cancer Therapy
- #Apoptosis
- #BCL-2
- BCL-2 was initially discovered in chromosomal translocations linked to lymphoid malignancies.
- BCL-2 inhibits apoptosis by preventing mitochondrial outer membrane permeabilization (MOMP), which blocks cytochrome c release and caspase activation.
- The BCL-2 family includes anti-apoptotic proteins (e.g., BCL-2, BCL-XL) and pro-apoptotic proteins (e.g., BAX, BAK, BH3-only proteins), maintaining a balance in cell death regulation.
- MicroRNAs like miR-15/16, often deleted in chronic lymphocytic leukemia (CLL), regulate BCL-2 expression and contribute to oncogenesis.
- BAX/BAK oligomerization forms mitochondrial pores, with sublethal MOMP triggering inflammation via cGAS-STING and NF-κB pathways.
- The BCL-2 inhibitor venetoclax has revolutionized treatment for CLL and acute myeloid leukemia (AML), especially in TP53-mutant CLL and elderly AML patients when combined with other therapies.
- Resistance to BCL-2 inhibitors can arise from mutations (e.g., Gly101Val) or MCL-1 upregulation, posing clinical challenges.
- BCL-2 inhibitors have shown limited success in solid tumors, highlighting the complexity of BCL-2 family dependencies.
- Future research directions include novel inhibitors targeting MCL-1 or BCL-XL, BH3 profiling for precision therapy, and combinations with immune or DNA repair modulators.
- Non-apoptotic roles of BCL-2 in metabolism are an emerging area of interest.