A dual role for the anti-apoptotic Bcl-2 protein in cancer: mitochondria versus endoplasmic reticulum.
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.
KU 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. Electronic address: haidar.akl@med.kuleuven.be.
Haidar
H
Akl
KU 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.
Tamara
T
Vervloessem
KU 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.
Santeri
S
Kiviluoto
KU 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.
Mart
M
Bittremieux
KU 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.
Jan B
JB
Parys
KU 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.
Humbert
H
De Smedt
KU 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. Electronic address: geert.bultynck@med.kuleuven.be.
Geert
G
Bultynck
D017209:Apoptosis; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002470:Cell Survival; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*
D053496:Inositol 1,4,5-Trisphosphate Receptors; D019253:Proto-Oncogene Proteins c-bcl-2; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium
Apoptosis; Bcl-2; Ca(2+); Cancer B-cell; Cell cycle; Inositol 1,4,5-trisphosphate receptor