Targeting Apoptosis Signalling in Cancer: How Decreasing BAK Phosphorylation via BMX Inhibition Increases Sensitivity to Cytotoxic Drugs

Abstract

CommentaryAt the molecular level there exists a fine balance between death and survival, which is essential in healthy cells for normal foetal development and for the clearance of damaged cells. However, more often than not, this balance is disrupted in diseases resulting in either too much cell death, for example in neurodegenerative disorders, or insufficient cell death as observed in cancer. Cancers are genetically heterogeneous and evolve during tumourigenesis, a process that helps cancer cells survive, by evading cell death, promoting proliferation and activating migration and invasion [1]. Targeting apoptosis, particularly for the treatment of cancer, has therefore become an increasingly attractive intervention strategy. Drugs approved for clinical use as well as many in the development pipeline aim to alter apoptotic signalling outcome or to trigger initiation of apoptosis, for example SMAC mimetics or BH3 mimetic Venetoclax respectively. However, these approaches have not been without their complications with both ontarget and off-target dose limiting toxicity reported, as well as the development of drug-induced resistance (reviewed in [2]). Despite the exciting progress that has been made in understanding and targeting the complex pathways that commits a cell to die by apoptosis, it is becoming increasingly clear that simply characterising the effector pathways is not enough [2]. Understanding the regulatory pathways and checkpoints at the crucial commitment points that trigger these executioner cell death pathways is equally important and could be the key to enable successful modulation of death pathways that determine cell fate.Intrinsic or mitochondrial apoptosis depends on activation of the BCL-2 effector proteins BAK and/or BAX which, once activated, are able to form first dimers then higher order multimers which disrupts the outer mitochondrial membrane [3]. This loss of membrane integrity results in the release of apoptogenic factors such as cytochrome c which is required to form an active apoptosome complex and activates downstream caspases. Recent studies, however, have found that it is activation of BAK/BAX resulting in the loss of mitochondrial outer membrane potential (MOMP) as the irreversible commitment step in the process. Therefore, BAK/BAX exert their effects at a crucial point in the apoptotic cascade and regulation of their activation status is critical in determining cell fate. BAK is constitutively present in the outer mitochondrial membrane, and requires tight regulation to ensure that aberrant induction of apoptosis does not occur. Two key sequential dephosphorylation events serve to regulate the ability of BAK to undergo activation in response to death signals. The initial BAK dephosphorylation at Y108 by PTPN5 [4] is the key switch that enables BAK activation to proceed, followed by dephosphorylation of S116 by PP2A [5]. Once these two phosphorylation marks have been removed then BAK activation can proceed [3].In our recent article "BMX Negatively Regulates BAK Function Thereby...