The complex landscape of pancreatic cancer metabolism

Carcinogenesis

Volumn 35, Issue 7, 2014, Pages

  Sousa, Cristovão Marques ^a   Kimmelman, Alec C ^a  

^a HARVARD MEDICAL SCHOOL   (United States)

Author keywords

Autophagy; Fatty acids; Glucose; Glutamine; Kras; Metabolism; Pancreatic cancer; PDA; ROS

Indexed keywords

FATTY ACID; GLUTAMINE; K RAS PROTEIN; LIPID; NICOTINAMIDE ADENINE DINUCLEOTIDE; REACTIVE OXYGEN METABOLITE; TUMOR PROTEIN;

AMINO ACID SYNTHESIS; BIOSYNTHESIS; CANCER DIAGNOSIS; GLUCOSE METABOLISM; HUMAN; HYPOXIA; MACROAUTOPHAGY; METABOLISM; NONHUMAN; PANCREAS ADENOCARCINOMA; PINOCYTOSIS; PRIORITY JOURNAL; REVIEW; TUMOR SUPPRESSOR GENE; ANIMAL; GENE REGULATORY NETWORK; GENETICS; METABOLOMICS; PANCREAS TUMOR; PATHOLOGY; SIGNAL TRANSDUCTION;

ANIMALS; GENE REGULATORY NETWORKS; HUMANS; METABOLOMICS; NEOPLASM PROTEINS; PANCREATIC NEOPLASMS; SIGNAL TRANSDUCTION;

EID: 84903960967     PISSN: 01433334     EISSN: 14602180     Source Type: Journal    
DOI: 10.1093/carcin/bgu097     Document Type: Review

References (185)

1. Siegel, R. et al. (2013) Cancer Statistics, 2013. 63, 11-30.
2. SEER Cancer Statistics Factsheets: Pancreas Cancer. National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/statfacts/html/pancreas.html. [Online]. Available: Http://seer.cancer.gov/statfacts/html/pancreas.html.
3. Hidalgo, M. (2010) Pancreatic cancer. N. Engl. J. Med., 362, 1605-17.
4. Vincent, A. et al. (2011) Pancreatic cancer. Lancet, 378, 607-20.
5. Li, D. et al. (2004) Pancreatic cancer. Lancet, 363, 1049-57.
6. Erkan, M. et al. (2012) StellaTUM: Current consensus and discussion on pancreatic stellate cell research. Gut, 61, 172-8.
7. Chu, G.C. et al. (2007) Stromal biology of pancreatic cancer. J. Cell. Biochem., 101, 887-907.
8. Koong, a C. et al. (2000) Pancreatic tumors show high levels of hypoxia. Int. J. Radiat. Oncol. Biol. Phys., 48, 919-22.
9. Guillaumond, F. et al. (2013) Strengthened glycolysis under hypoxia supports tumor symbiosis and hexosamine biosynthesis in pancreatic adenocarcinoma. Proc. Natl. Acad. Sci. U. S. A., 110, 3919-24.
10. Olive, K.P. et al. (2009) Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science, 324, 1457-61.
11. Provenzano, P.P. et al. (2012) Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell, 21, 418-29.
12. Kimmelman, A.C. et al. (2008) Genomic alterations link Rho family of GTPases to the highly invasive phenotype of pancreas cancer. Proc. Natl. Acad. Sci. U. S. A., 105, 19372-7.
13. Campbell, P.J. et al. (2010) The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature, 467, 1109-13.
14. Li, Y.-H. et al. (2012) Inhibition of non-homologous end joining repair impairs pancreatic cancer growth and enhances radiation response. PLoS One, 7, e39588.
15. Ying, H. et al. (2012) Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell, 149, 656-70.
16. Son, J. et al. (2013) Glutamine supports pancreatic cancer growth through a KRASregulated metabolic pathway. Nature, 496, 101-5.
17. Lyssiotis, C. a et al. (2013) Pancreatic cancers rely on a novel glutamine metabolism pathway to maintain redox balance. Cell Cycle, 12, 1987-8.
18. Feig, C. et al. (2012) The pancreas cancer microenvironment. Clin. Cancer Res., 18, 4266-76.
19. Neesse, A. et al. (2011) Stromal biology and therapy in pancreatic cancer. Gut, 60, 861-8.
20. Apte, M. V et al. (2012) Pancreatic stellate cells: A starring role in normal and diseased pancreas. Front. Physiol., 3, 344.
21. Oberstein, P.E. et al. (2013) Pancreatic cancer: why is it so hard to treat? Therap. Adv. Gastroenterol., 6, 321-37.
22. Milosevic, M. et al. (2012) Tumor hypoxia predicts biochemical failure following radiotherapy for clinically localized prostate cancer. Clin. Cancer Res., 18, 2108-14.
23. Heller, a et al. (2010) Immunogenicity of SEREX-identified antigens and disease outcome in pancreatic cancer. Cancer Immunol. Immunother., 59, 1389-400.
24. Bazhin, A. V et al. (2013) Overcoming immunosuppression as a new immunotherapeutic approach against pancreatic cancer. Oncoimmunology, 2, e25736.
25. Bayne, L.J. et al. (2012) Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell, 21, 822-35.
26. Pylayeva-Gupta, Y. et al. (2012) Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia. Cancer Cell, 21, 836-47.
27. Clark, C.E. et al. (2007) Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res., 67, 9518-27.
28. Almoguera, C. et al. (1988) Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell, 53, 549-54.
29. Uemura, T. et al. (2004) Detection of K-ras mutations in the plasma DNA of pancreatic cancer patients. J. Gastroenterol., 39, 56-60.
30. Pylayeva-Gupta, Y. et al. (2011) RAS oncogenes: Weaving a tumorigenic web. Nat. Rev. Cancer, 11, 761-74.
31. Löhr, M. et al. (2005) Frequency of K-ras mutations in pancreatic intraductal neoplasias associated with pancreatic ductal adenocarcinoma and chronic pancreatitis: A metaanalysis. Neoplasia, 7, 17-23.
32. Campbell, P.M. et al. (2004) Oncogenic Ras and its role in tumor cell invasion and metastasis. Semin. Cancer Biol., 14, 105-14.
33. Cox, A.D. et al. (2010) Ras history: The saga continues. Small GTPases, 1, 2-27.
34. Aguirre, A.J. et al. (2003) Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev., 17, 3112-26.
35. Hingorani, S.R. et al. (2005) Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell, 7, 469-83.
36. Ijichi, H. et al. (2006) Aggressive pancreatic ductal adenocarcinoma in mice caused by pancreas-specific blockade of transforming growth factor-beta signaling in cooperation with active Kras expression. Genes Dev., 20, 3147-60.
37. Guerra, C. et al. (2007) Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell, 11, 291-302.
38. Gidekel Friedlander, S.Y. et al. (2009) Context-dependent transformation of adult pancreatic cells by oncogenic K-Ras. Cancer Cell, 16, 379-89.
39. Hingorani, S.R. et al. (2003) Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell, 4, 437-50.
40. Pellegata, N.S. et al. (1994) K-ras and p53 gene mutations in pancreatic cancer: Ductal and nonductal tumors progress through different genetic lesions. Cancer Res., 54, 1556-60.
41. Hezel, A.F. et al. (2006) Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev., 20, 1218-49.
42. Hudson, T.J. et al. (2010) International network of cancer genome projects. Nature, 464, 993-8.
43. Cowley, M.J. et al. (2013) Understanding pancreatic cancer genomes. J. Hepatobiliary. Pancreat. Sci., DOI: 10.1007/s00534-013-0610-6.
44. Biankin, A. V et al. (2012) Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature, 491, 399-405.
45. Yachida, S. et al. (2010) Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature, 467, 1114-7.
46. Vander Heiden, M.G. et al. (2009) Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science, 324, 1029-33.
47. Lunt, S.Y. et al. (2011) Aerobic glycolysis: Meeting the metabolic requirements of cell proliferation. Annu. Rev. Cell Dev. Biol., 27, 441-64.
48. Hanahan, D. et al. (2011) Hallmarks of cancer: The next generation. Cell, 144, 646-74.
49. Vander Heiden, M.G. (2011) Targeting cancer metabolism: A therapeutic window opens. Nat. Rev. Drug Discov., 10, 671-84.
50. Ward, P.S. et al. (2012) Metabolic reprogramming: A cancer hallmark even warburg did not anticipate. Cancer Cell, 21, 297-308.
51. Le, A. et al. (2012) Conceptual framework for cutting the pancreatic cancer fuel supply. Clin. Cancer Res., 18, 4285-90.
52. White, E. (2013) Exploiting the bad eating habits of Ras-driven cancers. Genes Dev., 27, 2065-71.
53. DeBerardinis, R.J. et al. (2008) The biology of cancer: Metabolic reprogramming fuels cell growth and proliferation. Cell Metab., 7, 11-20.
54. Hensley, C.T. et al. (2013) Glutamine and cancer: Cell biology, physiology, and clinical opportunities. J. Clin. Invest., 123, 3678-84.
55. Fan, J. et al. (2013) Glutamine-driven oxidative phosphorylation is a major ATP source in transformed mammalian cells in both normoxia and hypoxia. Mol. Syst. Biol., 9, 1-11.
56. Yang, Z. et al. (2010) Eaten alive: A history of macroautophagy. Nat. Publ. Gr., 12, 814-822.
57. Levine, B. et al. (2008) Autophagy in the pathogenesis of disease. Cell, 132, 27-42.
58. Kroemer, G. et al. (2010) Autophagy and the integrated stress response. Mol. Cell, 40, 280-93.
59. Mizushima, N. et al. (2011) The role of Atg proteins in autophagosome formation. Annu. Rev. Cell Dev. Biol., 27, 107-32.
60. Boya, P. et al. (2013) Emerging regulation and functions of autophagy. Nat. Cell Biol., 15, 713-20.
61. Das, G. et al. (2012) Regulation and function of autophagy during cell survival and cell death. Cold Spring Harb. Perspect. Biol., 4, 1-14.
62. Klionsky, D.J. et al. (2011) A comprehensive glossary of autophagy-related molecules and processes (2nd edition). Autophagy, 7, 1273-94.
63. Yang, Z. et al. (2010) Mammalian autophagy: Core molecular machinery and signaling regulation. Curr. Opin. Cell Biol., 22, 124-31.
64. Neufeld, T.P. (2010) TOR-dependent control of autophagy: Biting the hand that feeds. Curr. Opin. Cell Biol., 22, 157-68.
65. Dodson, M. et al. (2013) Cellular metabolic and autophagic pathways: Traffic control by redox signaling. Free Radic. Biol. Med., 63, 207-21.
66. Rodriguez-Rocha, H. et al. (2011) DNA damage and autophagy. Mutat. Res., 711, 158-66.
67. Kimmelman, A.C. (2011) The dynamic nature of autophagy in cancer. Genes Dev., 25, 1999-2010.
68. White, E. (2012) Deconvoluting the context-dependent role for autophagy in cancer. Nat. Rev. Cancer, 12, 401-10.
69. Degenhardt, K. et al. (2006) Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell, 10, 51-64.
70. Rabinowitz, J.D. et al. (2010) Autophagy and metabolism. Science, 330, 1344-8.
71. Amaravadi, R.K. et al. (2011) Principles and current strategies for targeting autophagy for cancer treatment. Clin. Cancer Res., 17, 654-66.
72. Sui, X. et al. (2013) Autophagy and chemotherapy resistance: A promising therapeutic target for cancer treatment. Cell Death Dis., 4, e838.
73. Samaddar, J.S. et al. (2008) A role for macroautophagy in protection against 4-hydroxytamoxifen-induced cell death and the development of antiestrogen resistance. Mol. Cancer Ther., 7, 2977-87.
74. Amaravadi, R.K. et al. (2007) Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J. Clin. Invest., 117, 326-36.
75. Wang, P. et al. (2013) MicroRNA 23b regulates autophagy associated with radioresistance of pancreatic cancer cells. Gastroenterology, 145, 1133-1143.e12.
76. Liu, E.Y. et al. (2012) Autophagy and cancer--issues we need to digest. J. Cell Sci., 125, 2349-58.
77. Yang, S. et al. (2011) Pancreatic cancers require autophagy for tumor growth. Genes Dev., 25, 717-29.
78. Guo, J. et al. (2013) Autophagy is required for mitochondrial function, lipid metabolism, growth and fate of KRAS G12D-driven lung tumors. Autophagy, 9, 1636-1638.
79. Kim, M.-J. et al. (2011) Involvement of autophagy in oncogenic K-Ras-induced malignant cell transformation. J. Biol. Chem., 286, 12924-32.
80. Lock, R. et al. (2011) Autophagy facilitates glycolysis during Ras-mediated oncogenic transformation. Mol. Biol. Cell, 22, 165-78.
81. Guo, J.Y. et al. (2011) Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev., 25, 460-70.
82. Wei, H. et al. (2011) Suppression of autophagy by FIP200 deletion inhibits mammary tumorigenesis. Genes Dev., 25, 1510-27.
83. McMahon, H.T. et al. (2011) Molecular mechanism and physiological functions of clathrinmediated endocytosis. Nat. Rev. Mol. Cell Biol., 12, 517-33.
84. Swanson, J. et al. (1995) Macropinocytosis. Trends Cell Biol., 5, 424-428.
85. Lim, J.P. et al. (2011) Macropinocytosis: An endocytic pathway for internalising large gulps. Immunol. Cell Biol., 89, 836-43.
86. Bar-Sagi, D. et al. (1986) Induction of membrane ruffling and fluid-phase pinocytosis in quiescent fibroblasts by ras proteins. Science, 233, 1061-8.
87. Commisso, C. et al. (2013) Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature, 497, 633-7.
88. Kamphorst, J.J. et al. (2013) Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids. Proc. Natl. Acad. Sci. U. S. A., 110, 8882-7.
89. Berg, J.M. et al. (2002) Biochemistry, (5th edn) W.H. Freeman.
90. Vander Heiden, M.G. et al. (2011) Metabolic pathway alterations that support cell proliferation. Cold Spring Harb. Symp. Quant. Biol., 76, 325-34.
91. Von Hoff, D.D. et al. (2013) Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N. Engl. J. Med., 369, 1691-703.
92. Yun, J. et al. (2009) Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science, 325, 1555-9.
93. Gaglio, D. et al. (2011) Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth. Mol. Syst. Biol., 7, 523.
94. Racker, E. et al. (1985) Glycolysis and methylaminoisobutyrate uptake in rat-1 cells transfected with ras or myc oncogenes. Proc. Natl. Acad. Sci. U. S. A., 82, 3535-8.
95. Chun, S.Y. et al. (2010) Oncogenic KRAS modulates mitochondrial metabolism in human colon cancer cells by inducing HIF-1α and HIF-2α target genes. Mol. Cancer, 9, 293.
96. Zhao, D. et al. (2013) Lysine-5 acetylation negatively regulates lactate dehydrogenase A and is decreased in pancreatic cancer. Cancer Cell, 23, 464-76.
97. Icard, P. et al. (2012) A global view of the biochemical pathways involved in the regulation of the metabolism of cancer cells. Biochim. Biophys. Acta, 1826, 423-33.
98. Slawson, C. et al. (2010) O-GlcNAc signaling: A metabolic link between diabetes and cancer? Trends Biochem. Sci., 35, 547-55.
99. Hanover, J.A. et al. (2010) The hexosamine signaling pathway: O-GlcNAc cycling in feast or famine. Biochim. Biophys. Acta, 1800, 80-95.
100. KORNFELD, S. et al. (1964) THE FEEDBACK CONTROL OF SUGAR NUCLEOTIDE BIOSYNTHESIS IN LIVER. Proc. Natl. Acad. Sci. U. S. A., 52, 371-9.
101. Wellen, K.E. et al. (2010) The hexosamine biosynthetic pathway couples growth factorinduced glutamine uptake to glucose metabolism. Genes Dev., 24, 2784-99.
102. Mi, W. et al. (2011) O-GlcNAcylation is a novel regulator of lung and colon cancer malignancy. Biochim. Biophys. Acta, 1812, 514-9.
103. Fuster, M.M. et al. (2005) The sweet and sour of cancer: Glycans as novel therapeutic targets. Nat. Rev. Cancer, 5, 526-42.
104. Hart, G.W. et al. (2010) Glycomics hits the big time. Cell, 143, 672-6.
105. Jänne, P.A. et al. (2013) Selumetinib plus docetaxel for KRAS-mutant advanced non-smallcell lung cancer: A randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol., 14, 38-47.
106. Ghadimi, H. et al. (1964) Free Amino Acids of Cord Plasma As Compared With Maternal Plasma During Pregnancy. Pediatrics, 33, 500-6.
107. Wise, D.R. et al. (2010) Glutamine addiction: A new therapeutic target in cancer. Trends Biochem. Sci., 35, 427-33.
108. DeBerardinis, R.J. et al. (2010) Q's next: The diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene, 29, 313-24.
109. Metallo, C.M. et al. (2012) Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature, 481, 380-4.
110. Wise, D.R. et al. (2011) Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α -ketoglutarate to citrate to support cell growth and viability. Proc. Natl. Acad. Sci. U. S. A., 108, 19611-6.
111. DeBerardinis, R.J. et al. (2007) 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., 104, 19345-50.
112. Sinha, K. et al. (2013) Oxidative stress: The mitochondria-dependent and mitochondriaindependent pathways of apoptosis. Arch. Toxicol., 87, 1157-80.
113. Imlay, J. a et al. (1988) DNA damage and oxygen radical toxicity. Science, 240, 1302-9.
114. Sosa, V. et al. (2013) Oxidative stress and cancer: An overview. Ageing Res. Rev., 12, 376-90.
115. Hurd, T.R. et al. (2012) Redox regulation of cell migration and adhesion. Trends Cell Biol., 22, 107-15.
116. Iles, K.E. et al. (2002) Macrophage signaling and respiratory burst. Immunol. Res., 26, 95-105.
117. Sena, L.A. et al. (2012) Physiological roles of mitochondrial reactive oxygen species. Mol. Cell, 48, 158-67.
118. Fruehauf, J.P. et al. (2007) Reactive oxygen species: A breath of life or death? Clin. Cancer Res., 13, 789-94.
119. Cui, X. (2012) Reactive oxygen species: The achilles' heel of cancer cells? Antioxid. Redox Signal., 16, 1212-4.
120. Liou, G.-Y. et al. (2010) Reactive oxygen species in cancer. Free Radic. Res., 44, 479-96.
121. Storz, P. (2005) Reactive oxygen species in tumor progression. Front. Biosci., 10, 1881-96.
122. Pani, G. et al. (2010) Metastasis: Cancer cell's escape from oxidative stress. Cancer Metastasis Rev., 29, 351-78.
123. Weinberg, F. et al. (2010) Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc. Natl. Acad. Sci. U. S. A., 107, 8788-93.
124. Du, J. et al. (2013) Regulation of pancreatic cancer growth by superoxide. Mol. Carcinog., 52, 555-67.
125. Romanowska, M. et al. (2007) DNA damage, superoxide, and mutant K-ras in human lung adenocarcinoma cells. Free Radic. Biol. Med., 43, 1145-55.
126. Calvert, R.J. et al. (2013) K-ras 4A and 4B mRNA levels correlate with superoxide in lung adenocarcinoma cells, while at the protein level, only mutant K-ras 4A protein correlates with superoxide. Lung Cancer, 80, 263-9.
127. Vaquero, E.C. et al. (2004) Reactive oxygen species produced by NAD(P)H oxidase inhibit apoptosis in pancreatic cancer cells. J. Biol. Chem., 279, 34643-54.
128. Trachootham, D. et al. (2008) Redox regulation of cell survival. Antioxid. Redox Signal., 10, 1343-74.
129. Shelton, P. et al. (2013) The transcription factor NF-E2-related factor 2 (Nrf2): A protooncogene? FASEB J., 27, 414-23.
130. Hayes, J.D. et al. (2009) NRF2 and KEAP1 mutations: Permanent activation of an adaptive response in cancer. Trends Biochem. Sci., 34, 176-88.
131. DeNicola, G.M. et al. (2011) Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature, 475, 106-9.
132. Lister, A. et al. (2011) Nrf2 is overexpressed in pancreatic cancer: Implications for cell proliferation and therapy. Mol. Cancer, 10, 37.
133. Semenza, G.L. (2013) HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J. Clin. Invest., 123, 3664-71.
134. Zhao, F. et al. (2010) Imatinib resistance associated with BCR-ABL upregulation is dependent on HIF-1alpha-induced metabolic reprograming. Oncogene, 29, 2962-72.
135. Dang, C. V (2007) The interplay between MYC and HIF in the Warburg effect. Ernst Schering Found. Symp. Proc., at < http://www.ncbi.nlm.nih.gov/pubmed/18811052> .
136. Chaika, N. V et al. (2012) MUC1 mucin stabilizes and activates hypoxia-inducible factor 1 alpha to regulate metabolism in pancreatic cancer. Proc. Natl. Acad. Sci. U. S. A., 109, 13787-92.
137. Chen, C. et al. (2009) siRNA targeting HIF-1alpha induces apoptosis of pancreatic cancer cells through NF-kappaB-independent and-dependent pathways under hypoxic conditions. Anticancer Res., 29, 1367-72.
138. Chen, J. et al. (2003) Dominant-negative hypoxia-inducible factor-1 alpha reduces tumorigenicity of pancreatic cancer cells through the suppression of glucose metabolism. Am. J. Pathol., 162, 1283-91.
139. Wilkinson, S. et al. (2009) Hypoxia-selective macroautophagy and cell survival signaled by autocrine PDGFR activity. Genes Dev., 23, 1283-8.
140. Zhang, H. et al. (2008) Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J. Biol. Chem., 283, 10892-903.
141. Rausch, V. et al. (2012) Autophagy mediates survival of pancreatic tumour-initiating cells in a hypoxic microenvironment. J. Pathol., 227, 325-35.
142. Guerra, C. et al. (2013) Genetically engineered mouse models of pancreatic adenocarcinoma. Mol. Oncol., 7, 232-47.
143. Levine, A.J. et al. (2010) The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science, 330, 1340-4.
144. Harris, C.C. (1996) P53 Tumor Suppressor Gene: From the Basic Research Laboratory To the Clinic--an Abridged Historical Perspective. Carcinogenesis, 17, 1187-98.
145. Kruse, J.-P. et al. (2009) Modes of p53 regulation. Cell, 137, 609-22.
146. Levine, A. et al. (1991) The p53 tumour suppressor gene. Nature, 351, 453-456.
147. Aylon, Y. et al. (2007) Living with p53, dying of p53. Cell, 130, 597-600.
148. Scarpa, a et al. (1993) Pancreatic adenocarcinomas frequently show p53 gene mutations. Am. J. Pathol., 142, 1534-43.
149. Oshima, M. et al. (2013) Immunohistochemically detected expression of 3 major genes (CDKN2A/p16, TP53, and SMAD4/DPC4) strongly predicts survival in patients with resectable pancreatic cancer. Ann. Surg., 258, 336-46.
150. Pé rez-Mancera, P. a et al. (2012) What we have learned about pancreatic cancer from mouse models. Gastroenterology, 142, 1079-92.
151. Gottlieb, E. et al. (2010) P53 Regulation of Metabolic Pathways. Cold Spring Harb. Perspect. Biol., 2, a001040.
152. Shen, L. et al. (2012) The fundamental role of the p53 pathway in tumor metabolism and its implication in tumor therapy. Clin. Cancer Res., 18, 1561-7.
153. Illuzzi, J.L. et al. (2011) Modifications of p53 and the DNA damage response in cells expressing mutant form of the protein huntingtin. J. Mol. Neurosci., 45, 256-68.
154. Johnson, R.F. et al. (2012) Nuclear factor-κ B, p53, and mitochondria: Regulation of cellular metabolism and the Warburg effect. Trends Biochem. Sci., 37, 317-24.
155. Madan, E. et al. (2011) Regulation of glucose metabolism by p53: Emerging new roles for the tumor suppressor. Oncotarget, 2, 948-957.
156. Matoba, S. et al. (2006) P53 Regulates Mitochondrial Respiration. Science, 312, 1650-3.
157. Suzuki, S. et al. (2010) Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species. Proc. Natl. Acad. Sci. U. S. A., 107, 7461-6.
158. Hu, W. et al. (2010) Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. Proc. Natl. Acad. Sci. U. S. A., 107, 7455-60.
159. Kondoh, H. et al. (2005) Glycolytic enzymes can modulate cellular life span. Cancer Res., 65, 177-85.
160. Schwartzenberg-Bar-Yoseph, F. et al. (2004) The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression. Cancer Res., 64, 2627-33.
161. Bensaad, K. et al. (2006) TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell, 126, 107-20.
162. Jiang, P. et al. (2011) p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase. Nat. Cell Biol., 13, 310-6.
163. Rosenfeldt, M.T. et al. (2013) p53 status determines the role of autophagy in pancreatic tumour development. Nature, 504, 296-300.
164. Lizcano, J.M. et al. (2004) LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. EMBO J., 23, 833-43.
165. Lüttges, J. et al. (2004) Rare ductal adenocarcinoma of the pancreas in patients younger than age 40 years. Cancer, 100, 173-82.
166. Morton, J.P. et al. (2010) LKB1 haploinsufficiency cooperates with Kras to promote pancreatic cancer through suppression of p21-dependent growth arrest. Gastroenterology, 139, 586-97, 597.e1-6.
167. Inoki, K. et al. (2003) Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev., 17, 1829-34.
168. Yuan, H.-X. et al. (2013) Nutrient sensing, metabolism, and cell growth control. Mol. Cell, 49, 379-87.
169. Mihaylova, M.M. et al. (2011) The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat. Cell Biol., 13, 1016-23.
170. Jeon, S. et al. (2012) AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature, 485, 661-665.
171. Guo, J.Y. et al. (2013) Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis. Genes Dev., 27, 1447-61.
172. Zadra, G. et al. (2013) The fat side of prostate cancer. Biochim. Biophys. Acta, 1831, 1518-32.
173. Ma, X. et al. (2011) The metabolic features of normal pancreas and pancreatic adenocarcinoma: Preliminary result of in vivo proton magnetic resonance spectroscopy at 3.0 T. J. Comput. Assist. Tomogr., 35, 539-43.
174. Yabushita, S. et al. (2013) Metabolomic and transcriptomic profiling of human K-ras oncogene transgenic rats with pancreatic ductal adenocarcinomas. Carcinogenesis, 34, 1251-9.
175. Zhang, G. et al. (2013) Integration of metabolomics and transcriptomics revealed a fatty acid network exerting growth inhibitory effects in human pancreatic cancer. Clin. Cancer Res., 19, 4983-93.
176. Mohammed, A. et al. (2012) Endogenous n-3 polyunsaturated fatty acids delay progression of pancreatic ductal adenocarcinoma in Fat-1-p48(Cre/+)-LSL-Kras(G12D/+) mice. Neoplasia, 14, 1249-59.
177. Philip, B. et al. (2013) A High-Fat Diet Activates Oncogenic Kras and COX2 to Induce Development of Pancreatic Ductal Adenocarcinoma in Mice. Gastroenterology, 145, 1449-58.
178. Wang, F. et al. (2009) Increased lipid metabolism and cell turnover of MiaPaCa2 cells induced by high-fat diet in an orthotopic system. Metabolism., 58, 1131-6.
179. Pierre, A.-S. et al. (2013) Trans-10, cis-12 conjugated linoleic acid induced cell death in human colon cancer cells through reactive oxygen species-mediated ER stress. Biochim. Biophys. Acta, 1831, 759-68.
180. Di Stefano, M. et al. (2013) Diversification of NAD biological role: The importance of location. FEBS J., 280, 4711-28.
181. Chiarugi, A. et al. (2012) The NAD metabolome--a key determinant of cancer cell biology. Nat. Rev. Cancer, 12, 741-52.
182. Garten, A. et al. (2009) Nampt: Linking NAD biology, metabolism and cancer. Trends Endocrinol. Metab., 20, 130-8.
183. Billington, R.A. et al. (2008) NAD depletion by FK866 induces autophagy. Autophagy, 4, 385-7.
184. Chini, C.C.S. et al. (2013) Targeting of NAD Metabolism in Pancreatic Cancer Cells: Potential Novel Therapy for Pancreatic Tumors. Clin. Cancer Res., DOI: 10.1158/1078-0432.CCR-13-0150.
185. Von Heideman, A. et al. (2010) Safety and efficacy of NAD depleting cancer drugs: Results of a phase I clinical trial of CHS 828 and overview of published data. Cancer Chemother. Pharmacol., 65, 1165-72.