Cancer cells have fundamentally altered cellular metabolism that provide a biochemical foundation for tumors to progress in their etiology. These alterations include glycolytic addiction ("Warburg effect"), glutamine-dependent anaplerosis, and de novo lipid biosynthesis, which serve as metabolic platforms for supporting tumorigenicity. Although these factors are important in the transformation of cells from a non-cancerous to a cancerous state, much less is understood about the metabolic pathways that confer malignancy during tumor progression. Since most cancer deaths are related to cancer malignancy and metastasis, understanding metabolic pathways that contribute to these pathogenic features of cancer is critical for both diagnosis and treatment. Our efforts to profile the gene expression of broad panel of aggressive versus non-aggressive human cancer cells of multiple types have revealed a plethora of dysregulated metabolic enzymes whose expression is highly associated with cancer malignancy. These data point to a set of metabolic enzymes and pathways that may create key biochemical changes in cancer cells that support their progression to a high-malignancy state. Upon screening efforts to identify enzymes that, upon genetic knockdown, exhibit impaired cancer cell aggressiveness, we found that inactivation of inositol polyphosphate phosphatase 1 (INPP1) led to significant defects in cancer cell migration and invasiveness. From our preliminary results from metabolomic analyses of INPP1 inactivated cells, we interestingly find that INPP1 releases inositol phosphate, which then provides significant contributions to glycolytic intermediates, which are in-turn diverted towards biosynthesis of glycerophospholipids. These provocative results showing that glycolytic intermediates, instead of arising primarily from exogenous glucose, are generated from endogenous inositol phosphate metabolism, lead us to hypothesize that INPP1 inactivation may curb cancer malignancy by starving the cancer cell of glycolytic intermediates required for structural and oncogenic signaling lipids. This proposal will investigate the role of dysregulated inositol phosphate metabolism and INPP1 in driving the malignancy of human cancers and ascertain whether INPP1 inactivation may be an attractive strategy towards thwarting cancer progression. !
We have discovered an enzyme, INPP1 that drives the aggressiveness of multiple types of human cancers through biochemical conversion of inositol metabolism to sugar and lipid metabolic pathways. This proposal will investigate the role of dysregulated inositol phosphate metabolism and INPP1 in driving the malignancy of human cancers.
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