Voltage-Dependent Anion Channel 2 Controls Mitochondrial Priming through BAK Stabilization in Multiple Myeloma

• Published in: Blood 2024-11, Vol.144, p.3282-3282
• Main Authors: Champion, Ophélie, Maiga, Sophie, Dousset, Christelle, Aubry, Agnès, Bellanger, Céline, Guillonneau, François, Moreno, Jose Antonio, Kwon, Ohyun, Moreau, Philippe, Chiron, David, Pellat-Deceunynck, Catherine, Touzeau, Cyrille, Gomez-Bougie, Patricia
• Format: Article
• Language: English
• ISSN: 0006-4971
• DOI: 10.1182/blood-2024-194462

Evasion of apoptosis is an essential feature of cancer cells. The BCL2 family has emerged as a promising therapeutic target in cancer due to its ability to tightly regulate apoptosis. The BCL2 family encompasses anti and pro-apoptotic proteins that regulate themselves through protein-protein interactions, the balance between the two groups determines cell fate. Triggering of the apoptotic pathway involves the activation and oligomerization of the BCL2 pro-apoptotic effectors BAX and BAK, which ultimately causes a breach in the outer mitochondrial membrane. Complex mechanisms are involved in the regulation of these effector proteins. Beyond their sequestration by their anti-apoptotic BCL2 counterparts, non-BCL2 family proteins are emerging as partners of BAX and BAK and are considered as novel regulators of apoptosis. One of them is VDAC2, which belongs to the family of voltage dependent anion channels along with VDAC1 and VDAC3. VDAC2 is abundantly present in the mitochondrial outer membrane and has been implicated in apoptosis regulation. Nevertheless, it is not clear how this mechanistically occurs with contradictory evidence for the role in regulating BAX and BAK effectors. Notably, VDAC2 was reported necessary for efficient BAX dependent apoptosis, while conversely inhibits BAK apoptotic function. Multiple Myeloma (MM) is a B-cell neoplasia that overexpresses the anti-apoptotic BCL2 members. BAX and BAK effectors are also readily detected in MM patients' cells. Using 17 Human Myeloma Cell Lines (HMCLs) and 794 primary sample from the Multiple Myeloma Research Foundation (MMRF)-CoMMpass cohort, we found that VDAC1, VDAC2 and VDAC3 were heterogeneously expressed in MM cells. Interestingly, we found that low VDAC2 expression was associated with poor overall survival (OS) in this cohort. To understand why lower levels of VDAC2 were associated with poor OS, we generated VDAC2 KO myeloma cells. Notably, VDAC2 KO cells exhibited a drastic decrease of BAK protein expression while BAX remained unchanged. We demonstrated that VDAC2 regulated BAK protein expression by preventing its degradation through the proteasome and lysosome pathways. Accordingly, VDAC2 protein expression directly correlated with BAK but not with BAX protein levels and VDAC2 and BAK physically interacted at the mitochondria. Functionally, VDAC2 KO cells completely lost their mitochondrial priming and specific dependences on MCL1 and BCL2, which was due to the shortage of mitochondrial BAK. C