Chemical strategies for the global analysis of protein function: Profiling hydrolytic enzymes in cancer

Abstract

The molecular features specific to metastatic carcinomas that support their invasive behavior are complex and ill defined. Although one generally accepted notion assigns hydrolytic enzymes a central role in promoting the aggressive properties of metastatic tumors, the actual functions played by individual proteases and esterases in cancer remain elusive. To understand better how hydrolases and their endogenous inhibitors affect cancer, we are using a new chemical strategy, activity-based protein profiling. This method allows us to monitor simultaneously and directly the catalytic activities of numerous serine hydrolases from whole-cell, tissue and fluid samples. We have initiated a program to compare the serine hydrolase activity profiles of estrogen-receptor-positive and -negative human breast cancer cell lines. In breast carcinomas, a strong inverse correlation exists between estrogen receptor expression and several metastatic phenotypes, including cell invasiveness and motility. When this finding is coupled with the observation that serine protease inhibitors suppress estrogen-receptor-negative tumor cell migration and invasion, an intriguing model emerges in which serine hydrolases play a central role in mediating the aggressive behavior of these cells. Nonetheless, the identities of the participating enzymes remain unknown. Using activity-based protein profiling, we have identified several serine hydrolase activities that vary dramatically among these breast cancer lines. We anticipate that such studies will identify functional changes in key serine hydrolases involved in promoting or retarding tumorigenesis. These enzymes should in turn serve as both markers for cancer progression and targets for pharmaceutical efforts aimed at treating this disease.