A role for caspase-2 in sphingosine kinase 1 proteolysis in response to doxorubicin in breast cancer cells - implications for the CHK1-suppressed pathway.

Sphingosine kinase 1 (SK1) is a lipid kinase whose activity produces sphingosine 1-phosphate, a prosurvival lipid associated with proliferation, angiogenesis, and invasion. SK1 overexpression has been observed in numerous cancers. Recent studies have demonstrated that SK1 proteolysis occurs downstream of the tumor suppressor p53 in response to several DNA-damaging agents. Moreover, loss of SK1 in p53-knockout mice resulted in complete protection from thymic lymphoma, providing evidence that regulation of SK1 constitutes a major tumor suppressor function of p53. Given this profound phenotype, this study aimed to investigate the mechanism by which wild-type p53 regulates proteolysis of SK1 in response to the DNA-damaging agent doxorubicin in breast cancer cells. We find that p53-mediated activation of caspase-2 was required for SK1 proteolysis and that caspase-2 activity significantly alters the levels of endogenous sphingolipids. As p53 is mutated in 50% of all cancers, we extended our studies to investigate whether SK1 is deregulated in the context of triple-negative breast cancer cells (TNBC) harboring a mutation in p53. Indeed, caspase-2 was not activated in these cells and SK1 was not degraded. Moreover, caspase-2 activation was recently shown to be downstream of the CHK1-suppressed pathway in p53-mutant cells, whereby inhibition of the cell cycle kinase CHK1 leads to caspase-2 activation and apoptosis. Indeed, knockdown and inhibition of CHK1 led to the loss of SK1 in p53-mutant TNBC cells, providing evidence that SK1 may be the first identified effector of the CHK1-suppressed pathway.