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Tumor Biology

, Volume 37, Issue 5, pp 6027–6034 | Cite as

Inhibition of pentose phosphate pathway suppresses acute myelogenous leukemia

  • Yan Chen
  • Qian Xu
  • Dexiang Ji
  • Yanlin Wei
  • Huamei Chen
  • Tingting Li
  • Bolin Wan
  • Liya Yuan
  • Ruibin Huang
  • Guoan Chen
Original Article

Abstract

Pentose phosphate pathway (PPP) is a metabolic pathway that generates NADPH and pentose. PPP genes have been reported to be primarily or secondarily upregulated in many cancers. We aimed to study the general alteration of PPP in acute myelogenous leukemia (AML). We performed data mining and analysis of the Cancer Genome Atlas (TCGA) AML dataset for genetic alteration of the PPP gene set. In vitro studies including proliferation, migration, and invasion assays, together with metabolite consumption and oxidation assays, were performed. PPP genes were upregulated in 61 % of patients with AML. The majority of altered cases were expression changes measured by RNA sequencing. Expressions of critical PPP genes such as G6PD, PFKL, PFKP, and PGLS were consistently upregulated in all altered cases. Altered PPP is not associated with survival or disease relapse. PPP inhibition using 6-aminonicotinamide (6AN) increases glucose oxidative metabolism in AML. 6AN decreased the glucose oxidation and increased fatty acid oxidation. Here, we showed that PPP inhibition increased glucose oxidative metabolism in AML. PPP inhibition suppressed growth, migration, and invasion of AML, but not colony formation. PPP plays an important role in AML. Our results could contribute to the development of novel targeted treatment.

Keywords

Pentose phosphate pathway Acute myelogenous leukemia 6-Aminonicotinamide 

Notes

Acknowledgments

This study was supported in part by the International S&T Cooperation Program of China (Grant No. 2011DFA32820).

References

  1. 1.
    Dohner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015;373:1136–52.CrossRefPubMedGoogle Scholar
  2. 2.
    Borate UM, Mineishi S, Costa LJ. Nonbiological factors affecting survival in younger patients with acute myeloid leukemia. Cancer. 2015;121(21):3877–84.CrossRefPubMedGoogle Scholar
  3. 3.
    Cannella L, Caocci G, Jacobs M, Vignetti M, Mandelli F, Efficace F: Health-related quality of life and symptom assessment in randomized controlled trials of patients with leukemia and myelodysplastic syndromes: What have we learned? Crit Rev Oncol Hematol 2015Google Scholar
  4. 4.
    Wang ML, Bailey NG. Acute myeloid leukemia genetics: risk stratification and implications for therapy. Arch Pathol Lab Med. 2015;139:1215–23.CrossRefPubMedGoogle Scholar
  5. 5.
    Hefazi M, Siddiqui M, Patnaik M, Wolanskyj A, Alkhateeb H, Zblewski D, et al. : Prognostic impact of combined npm1+/flt3- genotype in patients with acute myeloid leukemia with intermediate risk cytogenetics stratified by age and treatment modalities. Leuk Res 2015Google Scholar
  6. 6.
    Stincone A, Prigione A, Cramer T, Wamelink MM, Campbell K, Cheung E, Olin-Sandoval V, et al.: The return of metabolism: Biochemistry and physiology of the pentose phosphate pathway. Biol Rev Camb Philos Soc 2014Google Scholar
  7. 7.
    Massari F, Ciccarese C, Santoni M, Brunelli M, Piva F, et al. Metabolic alterations in renal cell carcinoma. Cancer Treat Rev. 2015;41(9):767–76.CrossRefPubMedGoogle Scholar
  8. 8.
    Chen Y, Huang R, Ding J, Ji D, Song B, et al. Multiple myeloma acquires resistance to egfr inhibitor via induction of pentose phosphate pathway. Sci Rep. 2015;5:9925.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Parkhitko AA, Priolo C, Coloff JL, Yun J, Wu JJ, et al. Autophagy-dependent metabolic reprogramming sensitizes TSC2-deficient cells to the antimetabolite 6-aminonicotinamide. Mol Cancer Res. 2014;12:48–57.CrossRefPubMedGoogle Scholar
  10. 10.
    Cancer Genome Atlas Research N. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368:2059–74.CrossRefGoogle Scholar
  11. 11.
    Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:l1.CrossRefGoogle Scholar
  12. 12.
    Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401–4.CrossRefPubMedGoogle Scholar
  13. 13.
    Feng C, Ding G, Jiang H, Ding Q, Wen H. Loss of MLH1 confers resistance to PI3K beta inhibitors in renal clear cell carcinoma with SETD2 mutation. Tumour Biol. 2015;36:3457–64.CrossRefPubMedGoogle Scholar
  14. 14.
    Feng C, Sun Y, Ding G, Wu Z, Jiang H, et al. PI3K beta inhibitor TGX221 selectively inhibits renal cell carcinoma cells with both VHL and SETD2 mutations and links multiple pathways. Sci Rep. 2015;5:9465.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Esposito A, Criscitiello C, Gelao L, Pravettoni G, Locatelli M, Minchella I, et al. : Mechanisms of anorexia-cachexia syndrome and rational for treatment with selective ghrelin receptor agonist. Cancer Treat Rev 2015Google Scholar
  16. 16.
    Okon IS, Zou MH. Mitochondrial ROS and cancer drug resistance: implications for therapy. Pharmacol Res. 2015;100:170–4.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Patra KC, Hay N. The pentose phosphate pathway and cancer. Trends Biochem Sci. 2014;39:347–54.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Jiang P, Du W, Wu M. Regulation of the pentose phosphate pathway in cancer. Protein Cell. 2014;5:592–602.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Pedrosa AR, Graca JL, Carvalho S, Peleteiro MC, Duarte A, Trindade A: Notch signaling dynamics in the adult healthy prostate and in prostatic tumor development. The Prostate 2015Google Scholar
  20. 20.
    Lobry C, Oh P, Aifantis I. Oncogenic and tumor suppressor functions of Notch in cancer: it’s NOTCH what you think. J Exp Med. 2011;208:1931–5.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Yan Chen
    • 1
  • Qian Xu
    • 1
  • Dexiang Ji
    • 1
  • Yanlin Wei
    • 1
  • Huamei Chen
    • 1
  • Tingting Li
    • 1
  • Bolin Wan
    • 1
  • Liya Yuan
    • 2
  • Ruibin Huang
    • 1
  • Guoan Chen
    • 1
  1. 1.Department of HematologyThe First Affiliated Hospital of Nanchang UniversityNanchangChina
  2. 2.Department of HematologyJiangxi Academy of Medical ScienceNanchangChina

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