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Signaling and Targeting of 6-Phosphogluconate Dehydrogenase in Human Cancers

人类癌症中 6-磷酸葡萄糖酸脱氢酶的信号传导和靶向

基本信息

批准号：
8630691
负责人：
Jing Chen
金额：
$ 33.52万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-15 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8630691
关键词：
5&apos -AMP-activated protein kinase 6-phosphogluconate Acetyl-CoA Carboxylase Acetylation Acetylcysteine Anabolism Attenuated B-Cell Acute Lymphoblastic Leukemia Back Binding Bioenergetics Bone Marrow Transplantation Cancer cell line Cell Proliferation Cell Survival Cells Cervical Intraepithelial Neoplasia Clinical Treatment Colorectal Cancer Complex DNA biosynthesis Data Development Enzymes Evaluation H1299 Homeostasis Human In Vitro K-562 Laboratories Link Lysine Malignant Neoplasms Malignant neoplasm of lung Metabolic Metabolic Pathway Metabolism Modeling Mus NADP Normal Cell Nucleotide Biosynthesis Nude Mice Oxidation-Reduction Pathogenesis Pathway interactions Patients Pentosephosphate Pathway Pharmaceutical Preparations Phosphogluconate Dehydrogenase Phosphorylation Phosphorylation Inhibition Production Protein Kinase Inhibitors RNA RNA biosynthesis Reducing Agents Regulation Reporting Resistance Role STK11 gene Signal Transduction Signaling Molecule Testing Tissues Toxic effect Xenograft procedure base cancer cell in vivo inhibitor/antagonist leukemia lipid biosynthesis mimetics mutant next generation novel protein kinase inhibitor public health relevance ribulose 5-phosphate small hairpin RNA small molecule therapeutic target thyroid neoplasm tumor tumor growth tumor metabolism

项目摘要

Abstract: How cancer cells coordinate anabolic biosynthesis and redox homeostasis remains largely unknown. In normal cells, 6-phosphogluconate dehydrogenase (6PGD), an enzyme in the oxidative pentose phosphate pathway (PPP), converts 6-phosphogluconate (6-PG) to ribulose 5-phosphate (Ru-5-P) and produces NADPH. Upregulated 6PGD activity has been reported in several cancer tissues including colorectal cancers, cervical intraepithelial neoplasia and thyroid tumors, as well as leukemia (our unpublished data). However, how 6PGD is activated in human cancers and whether 6PGD activity is important in pathogenesis and tumor development remain unknown. We found that acetylation at K76 and K294 enhances 6PGD activation and is commonly observed in diverse human cancer cells. Stable knockdown of 6PGD in cancer cells results in reduced oxidative PPP flux and RNA/DNA biosynthesis. Surprisingly, 6PGD knockdown also causes decreased NADPH/NADP+ ratio, suggesting an important role for 6PGD in NADPH production that cannot be compensated by other NADPH-producing enzymes. Moreover, cancer cells with 6PGD knockdown show elevated ROS levels and aberrant biosynthesis, leading to reduced cell proliferation and tumor growth in xenograft nude mice. We next screened and identified Physcion as a novel, selective small molecule 6PGD inhibitor. Treatment with Physcion or its derivative S3 effectively inhibits cell proliferation in diverse human cancer cells with no off-target effect. Physcion and S3 also effectively inhibit cell viability and proliferation of primary leukemia cells from human patients with minimal toxicity. Furthermore, S3 significantly reduces tumor growth in xenograft nude mice subcutaneously injected with human H1299 lung cancer or K562 leukemia cells with minimal toxicity in vivo. Thus, we hypothesize that lysine acetylation enhances 6PGD activation, which promotes cancer cell proliferation and tumor growth; 6PGD thus represents a novel anti-cancer target in clinical treatment. Intriguingly, we also found that knockdown of 6PGD results in decreased intracellular levels of Ru-5-P (6PGD product), leading to activation of AMP-activated protein kinase (AMPK), which subsequently inhibits acetyl-CoA carboxylase 1 (ACC1) and consequently lipogenesis. Thus, in addition to the well-established connection between PPP and nucleotide biosynthesis, 6PGD provides a novel link between PPP, AMPK signaling and lipogenesis, which, along with the surprisingly crucial role for 6PGD in NADPH production and redox homeostasis, is important for cancer metabolism and tumor growth. We will test these hypotheses using human lung cancer and leukemias (CML, AML and B-ALL) as platforms. Three Specific Aims were proposed (1) To examine whether lysine acetylation is important for 6PGD activation and promotion of cancer cell metabolism and tumor growth; (2) To explore how 6PGD links PPP, AMPK signaling and lipogenesis to coordinate with redox regulation in promoting cancer cell metabolism and tumor growth; and (3) To validate 6PGD as an anti-leukemia target in treatment of human leukemia cells in vitro and in vivo using 6PGD small molecule inhibitors developed in our laboratory.

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