Abstract 2640: Small molecule compound NCI-8 induces ERK2-dependent mutant-p53 protein degradation

The tumor suppressor p53 is mutated in over 50% of human cancers leading not only to loss of wild-type p53 function, but also to gain-of-function (GOF) mutant p53 which acts as an oncogene. Mutant p53 is expressed at very high levels and can inhibit residual wild-type p53 activity as well as the function of p53 family member proteins such as p73 or p63. Therefore, targeting mutant p53 by either restoring the p53 pathway or depleting its GOF is an attractive strategy for cancer therapy. NCI-8 is a small molecule compound with dual abilities to induce p53 signal pathway and destabilize mutant p53 protein (deplete GOF) in mutant p53 expressing colorectal cancer cells. It remains unclear how NCI-8 regulates mutant p53 protein degradation. ERK2 is a member of the MAP kinase family which plays a critical role in regulating cell growth and differentiation by phosphorylating substrates including wild-type p53. We demonstrate that NCI-8-induces mutant p53 protein degradation via activation of ERK2 signaling. We observed a sustained phosphorylation of ERK2 upon NCI-8 treatment of cancer cells, but not in normal cells. MEK inhibitor U0126 treatment completely blocked NCI-8-mediated phosphorylation of ERK2 in cancer cells. These results, taken together, suggest that NCI-8 activates the ERK2 signaling pathway in cancer cells. There was a correlation between mutant p53 degradation and phosphorylation of ERK2 in cancer cells treated with NCI-8. We further examined the role of ERK2 phosphory...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Experimental and Molecular Therapeutics Source Type: research