Annotating the Role of Dysregulated Inositol Phosphate Metabolism in Malignant Ca

描述(申请人提供)：癌细胞已经从根本上改变了细胞代谢，为肿瘤的病因学进展提供了生化基础。这些改变包括糖酵解成瘾(“Warburg效应”)、谷氨酰胺依赖的逆转和从头脂肪生物合成，这些都是支持肿瘤发生的代谢平台。虽然这些因素在细胞从非癌变到癌变的过程中很重要，但人们对肿瘤进展过程中导致恶性的代谢途径知之甚少。由于大多数癌症死亡与癌症的恶性肿瘤和转移有关，了解导致癌症这些致病特征的代谢途径对于诊断和治疗都是至关重要的。我们对多种类型的侵袭性和非侵袭性人类癌细胞的基因表达进行了分析，发现了过多的代谢酶失调，它们的表达与癌症的恶性程度高度相关。这些数据指向一系列代谢酶和途径，这些代谢酶和途径可能会在癌细胞中产生关键的生化变化，支持它们向高度恶性状态发展。在筛选那些在基因敲除后表现出癌细胞侵袭性受损的酶的努力后，我们发现肌醇多聚磷酸酶1(INPP1)的失活会导致癌细胞迁移和侵袭性的显著缺陷。从我们对INPP1失活细胞的代谢分析的初步结果中，我们有趣地发现INPP1释放肌醇磷酸，然后提供重要的贡献给糖酵解中间体，而这些中间体又被转移到甘油磷脂的生物合成。这些具有挑衅性的结果表明，糖酵解中间体不是主要来自外源葡萄糖，而是内源性肌醇磷酸代谢产生的，这使我们假设INPP1失活可能通过饥饿癌细胞获得结构和致癌信号脂所需的糖酵解中间体来抑制癌症的恶性。这项建议将研究失调的肌醇磷酸代谢和INPP1在推动人类癌症恶性发展中的作用，并确定INPP1失活是否可能是阻止癌症进展的一种有吸引力的策略。好了！

DESCRIPTION (provided by applicant): 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. !