Abstract
Cancer cells possess fundamentally altered metabolism that supports their pathogenic features, which includes a heightened reliance on aerobic glycolysis to provide precursors for synthesis of biomass. We show here that inositol polyphosphate phosphatase 1 (INPP1) is highly expressed in aggressive human cancer cells and primary high-grade human tumors. Inactivation of INPP1 leads to a reduction in glycolytic intermediates that feed into the synthesis of the oncogenic signaling lipid lysophosphatidic acid (LPA), which in turn impairs LPA signaling and further attenuates glycolytic metabolism in a feed-forward mechanism to impair cancer cell motility, invasiveness, and tumorigenicity. Taken together these findings reveal a novel mode of glycolytic control in cancer cells that can serve to promote key oncogenic lipid signaling pathways that drive cancer pathogenicity.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Blotting, Western
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Carcinoma, Papillary / drug therapy
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Carcinoma, Papillary / metabolism
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Carcinoma, Papillary / pathology*
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Cell Movement / drug effects
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Cell Proliferation / drug effects
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Cystadenocarcinoma, Serous / drug therapy
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Cystadenocarcinoma, Serous / metabolism
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Cystadenocarcinoma, Serous / pathology*
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Female
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Glycolysis / drug effects*
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Humans
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Inositol Phosphates / pharmacology*
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Lipid Metabolism / drug effects*
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Metabolome / drug effects
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Mice
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Mice, SCID
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Neoplasms / drug therapy
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Neoplasms / metabolism
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Neoplasms / pathology
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Ovarian Neoplasms / drug therapy
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Ovarian Neoplasms / metabolism
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Ovarian Neoplasms / pathology*
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Phosphoric Monoester Hydrolases / antagonists & inhibitors
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Phosphoric Monoester Hydrolases / genetics
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Phosphoric Monoester Hydrolases / metabolism*
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RNA, Small Interfering / genetics
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Signal Transduction / drug effects
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Tumor Cells, Cultured
Substances
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Inositol Phosphates
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RNA, Small Interfering
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Phosphoric Monoester Hydrolases
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inositol-1,4-bisphosphate 1-phosphatase