Cisplatin reprogramming of protein phosphorylation

Cisplatin is a DNA-targeting chemotherapeutic. We have mapped cisplatin damage to specific genes in human lung cancer cells. Surprisingly, cisplatin targets the majority of protein kinase genes and protein phosphatase genes in the human genome. This suggests that cisplatin can reprogram protein phosphorylation genome-wide. We have profiled the protein expression and phosphorylation in human testicular cancer cells subjected to cisplatin treatment, since testicular cancer is curable by cisplatin. We demonstrate that most downregulated proteins are encoded by cisplatin damaged genes. These proteins include a series of protein kinases and protein phosphatases, leading to significant changes in the phosphorylation level of >600 proteins in testicular cancer cells. Hence, reprograming of protein phosphorylation is proteome-wide. Importantly, the reprogrammed protein phosphorylation activates G2/M DNA-damage checkpoint regulation and ATM signalling pathways, causing cell cycle arrest at the G2/M phase. These findings suggest that specific protein phosphorylation pathways are potential new targets for platinum drug design.