Activity-Based Protein Profiling of Oncogene-Driven Changes in Metabolism Reveals Broad Dysregulation of PAFAH1B2 and 1B3 in Cancer

Targeting dysregulated metabolic
pathways is a promising therapeutic strategy for eradicating cancer.
Understanding how frequently altered oncogenes regulate metabolic
enzyme targets would be useful in identifying both broad-spectrum
and targeted metabolic therapies for cancer. Here, we used activity-based
protein profiling to identify serine hydrolase activities that were
consistently upregulated by various human oncogenes. Through this
profiling effort, we found oncogenic regulatory mechanisms for several
cancer-relevant serine hydrolases and discovered that platelet activating
factor acetylhydrolase 1B2 and 1B3 (PAFAH1B2 and PAFAH1B3) activities
were consistently upregulated by several oncogenes, alongside previously
discovered cancer-relevant hydrolases fatty acid synthase and monoacylglycerol
lipase. While we previously showed that PAFAH1B2 and 1B3 were important
in breast cancer, our most recent profiling studies have revealed
that these enzymes may be dysregulated broadly across many types of
cancers. Here, we find that pharmacological blockade of both enzymes
impairs cancer pathogenicity across multiple different types of cancer
cells, including breast, ovarian, melanoma, and prostate cancer. We
also show that pharmacological blockade of PAFAH1B2 and 1B3 causes
unique changes in lipid metabolism, including heightened levels of
tumor-suppressing lipids. Our results reveal oncogenic regulatory
mechanisms of several cancer-relevant serine hydrolases using activity-based
protein profiling, and we show that PAFAH1B2 and 1B3 are important
in maintaining cancer pathogenicity across a wide spectrum of cancer
types.