Home LiteratureArticle Details
PMID: 24388967 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Review

KRAS: feeding pancreatic cancer proliferation.

Trends in biochemical sciences ·Vol. 39 ·No. 2 ·2014-02-00 ·Pages 91-100

Bryant KL, Mancias JD, Kimmelman AC, Der CJ

Abstract

Oncogenic KRAS mutation is the signature genetic event in the progression and growth of pancreatic ductal adenocarcinoma (PDAC), an almost universally fatal disease. Although it has been appreciated for some time that nearly 95% of PDAC harbor mutationally activated KRAS, to date no effective treatments that target this mutant protein have reached the clinic. A number of studies have shown that oncogenic KRAS plays a central role in controlling tumor metabolism by orchestrating multiple metabolic changes including stimulation of glucose uptake, differential channeling of glucose intermediates, reprogrammed glutamine metabolism, increased autophagy, and macropinocytosis. We review these recent findings and address how they may be applied to develop new PDAC treatments.

Keywords
autophagy glutaminolysis glycolysis macropinocytosis metabolism
MeSH Terms
Autophagy Carcinoma, Pancreatic Ductal/enzymology,genetics,pathology Cell Proliferation Gene Expression Regulation, Neoplastic Glucose/metabolism Glutamine/metabolism Humans Isoenzymes/genetics,metabolism Mutation Pancreatic Neoplasms/enzymology,genetics,pathology Pinocytosis Protein Structure, Tertiary Proto-Oncogene Proteins/genetics,metabolism Proto-Oncogene Proteins p21(ras) Signal Transduction ras Proteins/genetics,metabolism
Chemicals
Isoenzymes KRAS protein, human Proto-Oncogene Proteins Glutamine Proto-Oncogene Proteins p21(ras) ras Proteins Glucose
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Bryant Kirsten L
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Mancias Joseph D
Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA.
Kimmelman Alec C
Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA.
Der Channing J
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: cjder@med.unc.edu.
References (79)
79 references, click to expand
  1. K-ras codon-specific mutations produce distinctive metabolic phenotypes in NIH3T3 mice [corrected] fibroblasts.
    Cancer Res. 2005 Jul 1;65(13):5512-5 PMID: 15994921
  2. Ras-dependent carbon metabolism and transformation in mouse fibroblasts.
    Oncogene. 2006 Aug 31;25(39):5391-404 PMID: 16607279
  3. STK33 kinase activity is nonessential in KRAS-dependent cancer cells.
    Cancer Res. 2011 Sep 1;71(17):5818-26 PMID: 21742770
  4. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells.
    Nature. 2013 May 30;497(7451):633-7 PMID: 23665962
  5. Stromal biology and therapy in pancreatic cancer.
    Gut. 2011 Jun;60(6):861-8 PMID: 20966025
  6. Phosphofructokinase 1 glycosylation regulates cell growth and metabolism.
    Science. 2012 Aug 24;337(6097):975-80 PMID: 22923583
  7. The regulation of autophagy - unanswered questions.
    J Cell Sci. 2011 Jan 15;124(Pt 2):161-70 PMID: 21187343
  8. RAS oncogenes: weaving a tumorigenic web.
    Nat Rev Cancer. 2011 Oct 13;11(11):761-74 PMID: 21993244
  9. A unique platform for H-Ras signaling involving clathrin-independent endocytosis.
    Mol Biol Cell. 2008 Mar;19(3):765-75 PMID: 18094044
  10. Ras inhibition in glioblastoma down-regulates hypoxia-inducible factor-1alpha, causing glycolysis shutdown and cell death.
    Cancer Res. 2005 Feb 1;65(3):999-1006 PMID: 15705901
  11. Pancreatic tumors show high levels of hypoxia.
    Int J Radiat Oncol Biol Phys. 2000 Nov 1;48(4):919-22 PMID: 11072146
  12. Acquired glucose sensitivity of k-ras transformed fibroblasts.
    Biochem Soc Trans. 2005 Feb;33(Pt 1):297-9 PMID: 15667331
  13. Targeting mitochondrial glutaminase activity inhibits oncogenic transformation.
    Cancer Cell. 2010 Sep 14;18(3):207-19 PMID: 20832749
  14. Autophagy and metabolism.
    Science. 2010 Dec 3;330(6009):1344-8 PMID: 21127245
  15. Mammalian autophagy: core molecular machinery and signaling regulation.
    Curr Opin Cell Biol. 2010 Apr;22(2):124-31 PMID: 20034776
  16. Glutamine homeostasis and mitochondrial dynamics.
    Int J Biochem Cell Biol. 2009 Oct;41(10):2051-61 PMID: 19703661
  17. Hallmarks of cancer: the next generation.
    Cell. 2011 Mar 4;144(5):646-74 PMID: 21376230
  18. The dynamic nature of autophagy in cancer.
    Genes Dev. 2011 Oct 1;25(19):1999-2010 PMID: 21979913
  19. Principles and current strategies for targeting autophagy for cancer treatment.
    Clin Cancer Res. 2011 Feb 15;17(4):654-66 PMID: 21325294
  20. Aerobic glycolysis: meeting the metabolic requirements of cell proliferation.
    Annu Rev Cell Dev Biol. 2011;27:441-64 PMID: 21985671
  21. Differential activation of the Rac pathway by Ha-Ras and K-Ras.
    J Biol Chem. 2001 May 11;276(19):15609-15 PMID: 11278702
  22. Metabolism and action of amino acid analog anti-cancer agents.
    Pharmacol Ther. 1990;46(2):243-71 PMID: 2108451
  23. The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants.
    Science. 1997 Jul 18;277(5324):333-8 PMID: 9219684
  24. Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth.
    Mol Syst Biol. 2011 Aug 16;7:523 PMID: 21847114
  25. Hijacking a biosynthetic pathway yields a glycosyltransferase inhibitor within cells.
    Nat Chem Biol. 2011 Mar;7(3):174-81 PMID: 21258330
  26. Mitochondrial dysfunction contributes to oncogene-induced senescence.
    Mol Cell Biol. 2009 Aug;29(16):4495-507 PMID: 19528227
  27. Nutrition needs of mammalian cells in tissue culture.
    Science. 1955 Sep 16;122(3168):501-14 PMID: 13255879
  28. Small molecule inhibition of the KRAS-PDEδ interaction impairs oncogenic KRAS signalling.
    Nature. 2013 May 30;497(7451):638-42 PMID: 23698361
  29. The pre-hydrolysis state of p21(ras) in complex with GTP: new insights into the role of water molecules in the GTP hydrolysis reaction of ras-like proteins.
    Structure. 1999 Nov 15;7(11):1311-24 PMID: 10574788
  30. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis.
    Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19345-50 PMID: 18032601
  31. Proteomic analysis reveals Warburg effect and anomalous metabolism of glutamine in pancreatic cancer cells.
    J Proteome Res. 2012 Feb 3;11(2):554-63 PMID: 22050456
  32. Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity.
    Proc Natl Acad Sci U S A. 2012 Apr 3;109(14):5299-304 PMID: 22431598
  33. Hyper-O-GlcNAcylation is anti-apoptotic and maintains constitutive NF-κB activity in pancreatic cancer cells.
    J Biol Chem. 2013 May 24;288(21):15121-30 PMID: 23592772
  34. Glycolysis and methylaminoisobutyrate uptake in rat-1 cells transfected with ras or myc oncogenes.
    Proc Natl Acad Sci U S A. 1985 Jun;82(11):3535-8 PMID: 3858838
  35. Novel mechanism of inhibition of rat kidney-type glutaminase by bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES).
    Biochem J. 2007 Sep 15;406(3):407-14 PMID: 17581113
  36. Energy metabolism and proliferation in pancreatic carcinogenesis.
    Langenbecks Arch Surg. 2012 Apr;397(4):507-12 PMID: 22430298
  37. Ras oncogenes: split personalities.
    Nat Rev Mol Cell Biol. 2008 Jul;9(7):517-31 PMID: 18568040
  38. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis.
    Nature. 2011 Jul 06;475(7354):106-9 PMID: 21734707
  39. Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis.
    Genes Dev. 2011 Mar 1;25(5):460-70 PMID: 21317241
  40. Autophagy is activated in pancreatic cancer cells and correlates with poor patient outcome.
    Cancer Sci. 2008 Sep;99(9):1813-9 PMID: 18616529
  41. Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice.
    J Clin Invest. 2012 Feb;122(2):639-53 PMID: 22232209
  42. CD147 silencing inhibits lactate transport and reduces malignant potential of pancreatic cancer cells in in vivo and in vitro models.
    Gut. 2009 Oct;58(10):1391-8 PMID: 19505879
  43. Autophagy in cancer: good, bad, or both?
    Cancer Res. 2006 Oct 1;66(19):9349-51 PMID: 17018585
  44. STK33 kinase inhibitor BRD-8899 has no effect on KRAS-dependent cancer cell viability.
    Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):2860-5 PMID: 22323609
  45. Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells.
    Science. 2009 Sep 18;325(5947):1555-9 PMID: 19661383
  46. Understanding the Warburg effect: the metabolic requirements of cell proliferation.
    Science. 2009 May 22;324(5930):1029-33 PMID: 19460998
  47. Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia.
    Gastroenterology. 2012 Apr;142(4):730-733.e9 PMID: 22226782
  48. Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer.
    Cancer Cell. 2013 Aug 12;24(2):213-228 PMID: 23911236
  49. The Beclin 1 network regulates autophagy and apoptosis.
    Cell Death Differ. 2011 Apr;18(4):571-80 PMID: 21311563
  50. Autophagy mediates the mitotic senescence transition.
    Genes Dev. 2009 Apr 1;23(7):798-803 PMID: 19279323
  51. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity.
    Proc Natl Acad Sci U S A. 2010 May 11;107(19):8788-93 PMID: 20421486
  52. Ras history: The saga continues.
    Small GTPases. 2010 Jul;1(1):2-27 PMID: 21686117
  53. Reduction in the requirement of oncogenic Ras signaling to activation of PI3K/AKT pathway during tumor maintenance.
    Cancer Cell. 2005 Nov;8(5):381-92 PMID: 16286246
  54. In silico discovery of small-molecule Ras inhibitors that display antitumor activity by blocking the Ras-effector interaction.
    Proc Natl Acad Sci U S A. 2013 May 14;110(20):8182-7 PMID: 23630290
  55. Glutamine and cancer: cell biology, physiology, and clinical opportunities.
    J Clin Invest. 2013 Sep;123(9):3678-84 PMID: 23999442
  56. Oxidative stress in apoptosis and cancer: an update.
    Arch Toxicol. 2012 Nov;86(11):1649-65 PMID: 22811024
  57. Strengthened glycolysis under hypoxia supports tumor symbiosis and hexosamine biosynthesis in pancreatic adenocarcinoma.
    Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):3919-24 PMID: 23407165
  58. Discovery of small molecules that bind to K-Ras and inhibit Sos-mediated activation.
    Angew Chem Int Ed Engl. 2012 Jun 18;51(25):6140-3 PMID: 22566140
  59. HIF-1: upstream and downstream of cancer metabolism.
    Curr Opin Genet Dev. 2010 Feb;20(1):51-6 PMID: 19942427
  60. Glutamine addiction: a new therapeutic target in cancer.
    Trends Biochem Sci. 2010 Aug;35(8):427-33 PMID: 20570523
  61. Genetics and biology of pancreatic ductal adenocarcinoma.
    Genes Dev. 2006 May 15;20(10):1218-49 PMID: 16702400
  62. Autophagic activity dictates the cellular response to oncogenic RAS.
    Proc Natl Acad Sci U S A. 2012 Aug 14;109(33):13325-30 PMID: 22847423
  63. Pancreatic cancers require autophagy for tumor growth.
    Genes Dev. 2011 Apr 1;25(7):717-29 PMID: 21406549
  64. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy.
    Nat Med. 2011 Apr;17(4):500-3 PMID: 21460848
  65. Energy metabolism in tumor cells.
    FEBS J. 2007 Mar;274(6):1393-418 PMID: 17302740
  66. Links between metabolism and cancer.
    Genes Dev. 2012 May 1;26(9):877-90 PMID: 22549953
  67. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.
    Nature. 2012 Nov 15;491(7424):399-405 PMID: 23103869
  68. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway.
    Nature. 2013 Apr 4;496(7443):101-5 PMID: 23535601
  69. Oncogenic Ras-induced expression of Noxa and Beclin-1 promotes autophagic cell death and limits clonogenic survival.
    Mol Cell. 2011 Apr 8;42(1):23-35 PMID: 21353614
  70. Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by beta-phenylethyl isothiocyanate.
    Cancer Cell. 2006 Sep;10(3):241-52 PMID: 16959615
  71. Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression.
    Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2037-42 PMID: 20133848
  72. The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4.
    Cell. 2013 May 9;153(4):840-54 PMID: 23663782
  73. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism.
    Cell. 2012 Apr 27;149(3):656-70 PMID: 22541435
  74. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses.
    Science. 2008 Sep 26;321(5897):1801-6 PMID: 18772397
  75. Induction of membrane ruffling and fluid-phase pinocytosis in quiescent fibroblasts by ras proteins.
    Science. 1986 Sep 5;233(4768):1061-8 PMID: 3090687
  76. Regulation of glut1 mRNA by hypoxia-inducible factor-1. Interaction between H-ras and hypoxia.
    J Biol Chem. 2001 Mar 23;276(12):9519-25 PMID: 11120745
  77. Overview on how oncogenic Kras promotes pancreatic carcinogenesis by inducing low intracellular ROS levels.
    Front Physiol. 2013 Sep 12;4:246 PMID: 24062691
  78. Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids.
    Proc Natl Acad Sci U S A. 2013 May 28;110(22):8882-7 PMID: 23671091
  79. On the origin of cancer cells.
    Science. 1956 Feb 24;123(3191):309-14 PMID: 13298683
Article Info
Journal
Trends in biochemical sciences
Abbr.
Trends Biochem Sci
ISSN
0968-0004
DOI
10.1016/j.tibs.2013.12.004
Email
cjder@med.unc.edu
Published
2014-02-00
Epub
2014-00-02
Pages
91-100
Language
English
Region
England
NLM ID
7610674
PMCID
PMC3955735
Subset
IM
Grants
NCI NIH HHS · T32 CA71341 · United States
NCI NIH HHS · R01 CA042978 · United States
NCI NIH HHS · T32 CA009156 · United States
NCI NIH HHS · P30 CA016086 · United States
NCI NIH HHS · R01 CA157490 · United States
NCI NIH HHS · T32 CA071341 · United States
NCI NIH HHS · P50 CA127003 · United States
External Links
PubMed source DOI: 10.1016/j.tibs.2013.12.004 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2