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tissues including colorectal cancers, cervical intraepithelial neoplasia and thyroid tumors, as well as leukemia (our unpublished data).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.

Public Health Relevance

How cancer cells coordinate anabolic biosynthesis and appropriate redox status to provide an overall metabolic advantage to cancer cell proliferation and tumor growth remains largely unknown. Our hypothesis is that 6-phosphogluconate dehydrogenase (6PGD), an enzyme in the oxidative pentose phosphate pathway (PPP), is commonly activated by lysine acetylation in cancer cells to coordinate anabolic biosynthesis and redox homeostasis to promote cell proliferation and tumor development;6PGD also provides a novel link between PPP, AMPK signaling and lipogenesis. Thus, 6PGD represents a novel and common therapeutic target in clinical treatment of human cancers.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01CA174786-01A1
Application #
8630691
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Spalholz, Barbara A
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Fan, Jun; Lin, Ruiting; Xia, Siyuan et al. (2016) Tetrameric Acetyl-CoA Acetyltransferase 1 Is Important for Tumor Growth. Mol Cell 64:859-874
Gao, Xue; Lin, Shu-Hai; Ren, Feng et al. (2016) Acetate functions as an epigenetic metabolite to promote lipid synthesis under hypoxia. Nat Commun 7:11960
Elf, S; Lin, R; Xia, S et al. (2016) Targeting 6-phosphogluconate dehydrogenase in the oxidative PPP sensitizes leukemia cells to antimalarial agent dihydroartemisinin. Oncogene :
Kang, Hee-Bum; Fan, Jun; Lin, Ruiting et al. (2015) Metabolic Rewiring by Oncogenic BRAF V600E Links Ketogenesis Pathway to BRAF-MEK1 Signaling. Mol Cell 59:345-58
Wang, Jing; Luo, Cheng; Shan, Changliang et al. (2015) Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation. Nat Chem 7:968-79
Jin, Lingtao; Li, Dan; Alesi, Gina N et al. (2015) Glutamate dehydrogenase 1 signals through antioxidant glutathione peroxidase 1 to regulate redox homeostasis and tumor growth. Cancer Cell 27:257-70
Lin, Ruiting; Elf, Shannon; Shan, Changliang et al. (2015) 6-Phosphogluconate dehydrogenase links oxidative PPP, lipogenesis and tumour growth by inhibiting LKB1-AMPK signalling. Nat Cell Biol 17:1484-96
Shan, Changliang; Elf, Shannon; Ji, Quanjiang et al. (2014) Lysine acetylation activates 6-phosphogluconate dehydrogenase to promote tumor growth. Mol Cell 55:552-65
Fan, Jun; Shan, Changliang; Kang, Hee-Bum et al. (2014) Tyr phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate the pyruvate dehydrogenase complex. Mol Cell 53:534-48
Fan, Jun; Kang, Hee-Bum; Shan, Changliang et al. (2014) Tyr-301 phosphorylation inhibits pyruvate dehydrogenase by blocking substrate binding and promotes the Warburg effect. J Biol Chem 289:26533-41

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