VDAC2 primes myeloma cells for BAK-dependent apoptosis and represents a novel therapeutic target

Abstract

BAX and BAK, key executors of apoptosis from the BCL2 family [1], are also regulated by non-BCL2 family proteins, such as the mitochondrial channel VDAC2 [2]. Although well-recognized for its role in metabolite and ion flux [3], VDAC2 has drawn particular attention for its involvement in the regulation of apoptosis. VDAC2 was reported as being necessary for efficient BAX-dependent apoptosis [4], while inhibiting BAK apoptotic function [5]. BAX, but not BAK, is a well-known p53 target gene, and p53-mediated regulation of BAX is required for an optimal response to BH3-mimetics targeting BCL2 or MCL1 [6, 7]. In p53-deficient myeloma cells with low BAX expression, apoptosis is expected to rely on BAK expression and regulation. These data prompted us to investigate whether targeting VDAC2 would overcome the mitochondrial resistance of p53-deficient cells.

To investigate how VDAC2 influences mitochondrial apoptosis in multiple myeloma (MM), we performed transient silencing of VDAC2 in TP53-deficient human myeloma cell lines (HMCLs). Additionally, we evaluated the pharmacological targeting of VDAC2 in both MM cell lines and primary MM patient cells.