Related Experiment Video
Updated: Apr 30, 2026
Examining BCL-2 Family Function with Large Unilamellar Vesicles
Published on: October 5, 2012
A dual role for the anti-apoptotic Bcl-2 protein in cancer: mitochondria versus endoplasmic reticulum
Haidar Akl1, Tamara Vervloessem1, Santeri Kiviluoto1
1KU Leuven, Laboratory of Molecular and Cellular Signaling, Department of Molecular and Cellular Medicine, Campus Gasthuisberg, O/N-I, Bus 802, Herestraat 49, BE-3000 Leuven, Belgium.
Abstract:
Anti-apoptotic Bcl-2 contributes to cancer formation and progression by promoting the survival of altered cells. Hence, it is a prime target for novel specific anti-cancer therapeutics. In addition to its canonical anti-apoptotic role, Bcl-2 has an inhibitory effect on cell-cycle progression. Bcl-2 acts at two different intracellular compartments, the mitochondria and the endoplasmic reticulum (ER). At the mitochondria, Bcl-2 via its hydrophobic cleft scaffolds the Bcl-2-homology (BH) domain 3 (BH3) of pro-apoptotic Bcl-2-family members. Small molecules (like BH3 mimetics) can disrupt this interaction, resulting in apoptotic cell death in cancer cells. At the ER, Bcl-2 modulates Ca(2+) signaling, thereby promoting proliferation while increasing resistance to apoptosis. Bcl-2 at the ER acts via its N-terminal BH4 domain, which directly binds and inhibits the inositol 1,4,5-trisphosphate receptor (IP3R), the main intracellular Ca(2+)-release channel. Tools targeting the BH4 domain of Bcl-2 reverse Bcl-2's inhibitory action on IP3Rs and trigger pro-apoptotic Ca(2+) signaling in cancer B-cells, including chronic lymphocytic leukemia (CLL) cells and diffuse large B-cell lymphoma (DLBCL) cells. The sensitivity of DLBCL cells to BH4-domain targeting tools strongly correlated with the expression levels of the IP3R2 channel, the IP3R isoform with the highest affinity for IP3. Interestingly, bio-informatic analysis of a database of primary CLL patient cells also revealed a transcriptional upregulation of IP3R2. Finally, this review proposes a model, in which cancer cell survival depends on Bcl-2 at the mitochondria and/or the ER. This dependence likely will have an impact on their responses to BH3-mimetic drugs and BH4-domain targeting tools. This article is part of a Special Issue entitled: Calcium signaling in health and disease. Guest Editors: Geert Bultynck, Jacques Haiech, Claus W. Heizmann, Joachim Krebs, and Marc Moreau.
Insights
The anti-apoptotic protein Bcl-2 promotes cancer cell survival by inhibiting apoptosis and regulating cell cycle. Targeting Bcl-2
Area of Science:
- Cell Biology
- Molecular Oncology
- Cancer Therapeutics
Background:
- The anti-apoptotic protein Bcl-2 is crucial for cancer cell survival and progression.
- Bcl-2 functions at both mitochondria and the endoplasmic reticulum (ER) to inhibit apoptosis and promote proliferation.
- Bcl-2's dual localization and functions present it as a significant therapeutic target in oncology.
Purpose of the Study:
- To explore the dual role of Bcl-2 in cancer cell survival and its implications for therapeutic strategies.
- To investigate the mechanisms by which Bcl-2 at the ER modulates calcium signaling and affects cancer cell fate.
- To evaluate the potential of targeting the BH4 domain of Bcl-2 for cancer therapy, particularly in B-cell malignancies.
Main Methods:
- Review of existing literature on Bcl-2 function, localization, and interactions.
- Analysis of Bcl-2's role in modulating mitochondrial apoptotic pathways via BH3 domain interactions.
- Examination of Bcl-2's interaction with IP3R at the ER via the BH4 domain and its impact on calcium signaling.
Main Results:
- Bcl-2 inhibits apoptosis at the mitochondria by binding pro-apoptotic proteins and promotes proliferation at the ER by modulating Ca(2+) signaling through IP3R inhibition.
- Targeting the BH4 domain of Bcl-2 can reverse its inhibitory effect on IP3Rs, triggering pro-apoptotic Ca(2+) signaling.
- Sensitivity to BH4-domain targeting agents in diffuse large B-cell lymphoma (DLBCL) correlates with IP3R2 expression, which is also upregulated in chronic lymphocytic leukemia (CLL).
Conclusions:
- Cancer cell survival is dependent on Bcl-2's functions at both the mitochondria and ER.
- Targeting Bcl-2's BH4 domain offers a promising therapeutic strategy, especially for B-cell cancers like CLL and DLBCL.
- The expression levels of IP3R isoforms, particularly IP3R2, may predict patient response to Bcl-2-targeting therapies.
Related Concept Videos
01:31The Intrinsic Apoptotic Pathway
01:19Translocation of Proteins into the Mitochondria
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
01:22Cellular Injury V: Apoptosis and Autophagy
01:17The Extrinsic Apoptotic Pathway
01:32Export of Misfolded Proteins out of the ER
01:17Role of ER in the Secretory Pathway
Components of the secretory pathway
About a third of proteins synthesized in the cell are sorted via the secretory route. They shuffle between different compartments in membrane-bound vesicles until they reach their final destination. The main intracellular compartments involved...