Fig. 8
From: Src inhibition potentiates MCL-1 antagonist activity in acute myeloid leukemia
Schematic model of MCL-1/SRC inhibitor interactions in AML cells. MCL-1 antagonists, through a yet-to-be-determined mechanism, disrupt degradative MCL-1 ubiquitination, leading to MCL-1 stabilization, accumulation, and prevention of apoptosis. This phenomenon is antagonized by Src inhibitors, resulting in down-regulation of this anti-apoptotic protein (1). In addition, Src inhibitors counteract the activating phosphorylation of the STAT3 trasnscription factor, thereby inhibiting the transcription of multiple genes implicated in AML cell survival and proliferation e.g., BCL-xL, c-MYC, and MCL-1 (2). Moreover, combining Src and MCL-1 inhibitors leads to up-regulation of NOXA, a well-established promoter of MCL-1 degradation (3). Collectively, these events lead to dissociation of MCL-1 from BAX and BAK, thereby activating these proteins and triggering mitochondrial injury and apoptosis (4)
