B-cell lymphoma 2 (BCL-2) family and Caspase-3 (BCL2/CASP3)

The B-cell lymphoma 2 (BCL-2) family and Caspase-3 are integral regulators of the intrinsic (mitochondrial) pathway of apoptosis (StatPearls: Apoptosis). The BCL-2 family is divided into anti-apoptotic members like BCL-2 and MCL-1, and pro-apoptotic members like BAX and BAK (UniProt P10415). These proteins control the integrity of the mitochondrial outer membrane; their imbalance often leads to the release of cytochrome c into the cytosol. Once released, cytochrome c facilitates the activation of Caspase-3, a cysteine-aspartic acid protease known as the executioner caspase (UniProt P42574). Caspase-3 is responsible for the proteolytic cleavage of vital cellular proteins, leading to the morphological changes characteristic of cell death (PubMed: 10648661). In various cancers, the overexpression of anti-apoptotic BCL-2 proteins prevents the activation of Caspase-3, conferring a survival advantage to malignant cells. Therapeutic agents such as Venetoclax target BCL-2 to lower the threshold for apoptosis and trigger Caspase-3 activation in cancer cells (FDA: Venetoclax Label). This pathway is also implicated in neurodegenerative diseases where premature Caspase-3 activation leads to neuronal loss. Monitoring Caspase-3 activity and BCL-2 expression levels serves as a critical tool for assessing drug efficacy in clinical settings.

Other names

Bcl-2-like proteinsApoptosis pathway componentsCPP32ApopainSCA-1Cysteine-aspartic acid protease 3

Inhibition of anti-apoptotic BCL-2 family proteins (e.g., BCL-2, BCL-XL, MCL-1) to promote mitochondrial outer membrane permeabilization (MOMP), leading to the release of cytochrome c, activation of the apoptosome, and subsequent proteolytic activation of the executioner Caspase-3 to induce programmed cell death.