Mechanisms of Cisplatin-Induced Apoptosis and of Cisplatin Sensitivity: Potential of BIN1 to Act as a Potent Predictor of Cisplatin Sensitivity in Gastric Cancer Treatment
Figure 3
The molecular mechanism by which BIN1 is involved in cisplatin sensitization. Quoted from [5] and modified. The Miz-1-BIN1 interaction upregulates cellular cisplatin sensitivity by disruption of PARP1 activity. In cisplatin-sensitive cancer cells, a low level of c-Myc allows Miz-1 to stimulate BIN1 transcription, thereby maintaining a high cellular level of BIN1. The feedback inhibition of c-Myc by BIN1 perpetuates the decrease in c-Myc levels and results in decreased PARP1 activity, which consequently leads to downregulation of DNA repair activity. (b) In cisplatin-resistant cancer cells, c-Myc overexpression represses BIN1 expression by blocking the transcription activity of Miz-1. Loss of BIN1 feedback inhibition results in a robust increase in endogenous c-Myc and PARP1 activities, which consequently up-regulates DNA repair activity and cancer cell resistance to cisplatin. (a, b) Dashed lines indicate a decrease in the abundance or activity of a (positive or negative) regulator. Arrows indicate transcriptional up- or downregulation. Arrow size indicates the strength of this regulation.
