HIF-2α regulates non-canonical glutamine metabolism via activation of PI3K/mTORC2 pathway in human pancreatic ductal adenocarcinoma

Journal of Cellular and Molecular Medicine

Volumn 21, Issue 11, 2017, Pages 2896-2908

  Li, Wenzhu ^a   Chen, Changhao ^a   Zhao, Xiaohui ^a   Ye, Huilin ^a   Zhao, Yue ^b   Fu, Zhiqiang ^a   Pan, Wenwei ^b   Zheng, Shangyou ^a   Wei, Lusheng ^a   Nong, Tianwen ^a   Li, Zhihua ^a   Chen, Rufu ^a  

^a SUN YAT SEN MEMORIAL HOSPITAL OF SUN YAT SEN UNIVERSITY   (China)

^b THE FIRST AFFILIATED HOSPITAL OF SUN YAT SEN UNIVERSITY   (China)

Author keywords

HIF 2 ; non canonical glutamine metabolism; pancreatic ductal adenocarcinoma; pathway

Indexed keywords

ASPARTATE AMINOTRANSFERASE ISOENZYME 1; BETA ACTIN; GLUTAMINE; HYPOXIA INDUCIBLE FACTOR 2ALPHA; MAMMALIAN TARGET OF RAPAMYCIN; BASIC HELIX LOOP HELIX TRANSCRIPTION FACTOR; ENDOTHELIAL PAS DOMAIN-CONTAINING PROTEIN 1; GOT1 PROTEIN, HUMAN; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; PHOSPHATIDYLINOSITOL 3 KINASE; SMALL INTERFERING RNA;

ADULT; ARTICLE; CANCER GROWTH; CAPAN 2 CELL LINE; CARCINOGENICITY; CELL INVASION; CELL LINE; CELL MIGRATION; CELL PROLIFERATION; CFU COUNTING; FEMALE; FLOW CYTOMETRY; GENETIC TRANSFECTION; HUMAN; HUMAN EXPERIMENT; HUMAN TISSUE; IMMUNOHISTOCHEMISTRY; LYMPH NODE METASTASIS; MALE; MIDDLE AGED; PANC 1 CELL LINE; PANCREAS ADENOCARCINOMA; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; RNA ISOLATION; TUMOR BIOPSY; VIRUS INFECTION; WESTERN BLOTTING; WOUND HEALING ASSAY; AGED; ANIMAL; ANTAGONISTS AND INHIBITORS; CANCER STAGING; CANCER TRANSPLANTATION; CELL MOTION; GENE EXPRESSION REGULATION; GENETICS; METABOLISM; MORTALITY; NUDE MOUSE; PANCREAS CARCINOMA; PANCREAS TUMOR; PATHOLOGY; SIGNAL TRANSDUCTION; SURVIVAL ANALYSIS; TUMOR CELL LINE;

AGED; ANIMALS; ASPARTATE AMINOTRANSFERASE, CYTOPLASMIC; BASIC HELIX-LOOP-HELIX TRANSCRIPTION FACTORS; CARCINOMA, PANCREATIC DUCTAL; CELL LINE, TUMOR; CELL MOVEMENT; CELL PROLIFERATION; FEMALE; GENE EXPRESSION REGULATION, NEOPLASTIC; GLUTAMINE; HUMANS; LYMPHATIC METASTASIS; MALE; MECHANISTIC TARGET OF RAPAMYCIN COMPLEX 2; MICE, NUDE; MIDDLE AGED; NEOPLASM STAGING; NEOPLASM TRANSPLANTATION; PANCREATIC NEOPLASMS; PHOSPHATIDYLINOSITOL 3-KINASES; RNA, SMALL INTERFERING; SIGNAL TRANSDUCTION; SURVIVAL ANALYSIS;

EID: 85019905604     PISSN: 15821838     EISSN: None     Source Type: Journal    
DOI: 10.1111/jcmm.13202     Document Type: Article

References (35)

1. Wolfgang CL, Herman JM, Laheru DA, et al. Recent progress in pancreatic cancer. CA Cancer J Clin. 2013; 63: 318–48.
2. Hidalgo M. Pancreatic cancer. N Engl J Med. 2010; 362: 1605–17.
3. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; 144: 646–74.
4. Warburg O. On the origin of cancer cells. Science. 1956; 123: 309–14.
5. Hsu PP, Sabatini DM. Cancer cell metabolism: warburg and beyond. Cell. 2008; 134: 703–7.
6. Son J, Lyssiotis CA, Ying H, et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature. 2013; 496: 101–5.
7. Lyssiotis CA, Son J, Cantley LC, et al. Pancreatic cancers rely on a novel glutamine metabolism pathway to maintain redox balance. Cell Cycle. 2013; 12: 1987–8.
8. Phan LM, Yeung SC, Lee MH. Cancer metabolic reprogramming: importance, main features, and potentials for precise targeted anti-cancer therapies. Cancer Biol Med. 2014; 11: 1–19.
9. Asano T, Yao Y, Shin S, et al. Insulin receptor substrate is a mediator of phosphoinositide 3-kinase activation in quiescent pancreatic cancer cells. Cancer Res. 2005; 65: 9164–8.
10. Eser S, Reiff N, Messer M, et al. Selective requirement of PI3K/PDK1 signaling for Kras oncogene-driven pancreatic cell plasticity and cancer. Cancer Cell. 2013; 23: 406–20.
11. Asano T, Yao Y, Zhu J, et al. The rapamycin analog CCI-779 is a potent inhibitor of pancreatic cancer cell proliferation. Biochem Biophys Res Commun. 2005; 331: 295–302.
12. Pham NA, Schwock J, Iakovlev V, et al. Immunohistochemical analysis of changes in signaling pathway activation downstream of growth factor receptors in pancreatic duct cell carcinogenesis. BMC Cancer. 2008; 8: 43.
13. Shimobayashi M, Hall MN. Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat Rev Mol Cell Biol. 2014; 15: 155–62.
14. Lien EC, Lyssiotis CA, Cantley LC. Metabolic Reprogramming by the PI3K-Akt-mTOR Pathway in Cancer. Recent Results Cancer Res. 2016; 207: 39–72.
15. Toschi A, Lee E, Gadir N, et al. Differential dependence of hypoxia-inducible factors 1 alpha and 2 alpha on mTORC1 and mTORC2. J Biol Chem. 2008; 283: 34495–9.
16. Soares HP, Ming M, Mellon M, et al. Dual PI3K/mTOR Inhibitors Induce Rapid Overactivation of the MEK/ERK Pathway in Human Pancreatic Cancer Cells through Suppression of mTORC2. Mol Cancer Ther. 2015; 14: 1014–23.
17. Mohlin S, Hamidian A, von Stedingk K, et al. PI3K-mTORC2 but not PI3K-mTORC1 regulates transcription of HIF2A/EPAS1 and vascularization in neuroblastoma. Cancer Res. 2015; 75: 4617–28.
18. Dodd KM, Yang J, Shen MH, et al. mTORC1 drives HIF-1alpha and VEGF-A signalling via multiple mechanisms involving 4E-BP1, S6K1 and STAT3. Oncogene. 2015; 34: 2239–50.
19. Liu P, Cheng H, Roberts TM, et al. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discovery. 2009; 8: 627–44.
20. Maes C, Carmeliet G, Schipani E. Hypoxia-driven pathways in bone development, regeneration and disease. Nat Rev Rheumatol. 2012; 8: 358–66.
21. Majmundar AJ, Wong WJ, Simon MC. Hypoxia-inducible factors and the response to hypoxic stress. Mol Cell. 2010; 40: 294–309.
22. Fan J. HAF drives the switch of HIF-1α to HIF-2α by activating the NF-κB pathway, leading to malignant behavior of T24 bladder cancer cells. Int J Oncol. 2014; 44: 393–402.
23. Talks KL, Turley H, Gatter KC, et al. The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol. 2000; 157: 411–21.
24. Koh MY, Powis G. Passing the baton: the HIF switch. Trends Biochem Sci. 2012; 37: 364–72.
25. Wang Y, Shao N, Mao X, et al. MiR-4638-5p inhibits castration resistance of prostate cancer through repressing Kidins220 expression and PI3K/AKT pathway activity. Oncotarget. 2016; 7: 47444–64.
26. Semenza GL. HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J Clin Invest. 2013; 123: 3664–71.
27. Guillaumond F, Leca J, Olivares O, et al. Strengthened glycolysis under hypoxia supports tumor symbiosis and hexosamine biosynthesis in pancreatic adenocarcinoma. Proc Natl Acad Sci USA. 2013; 110: 3919–24.
28. Koong AC, Mehta VK, Le QT, et al. Pancreatic tumors show high levels of hypoxia. Int J Radiat Oncol Biol Phys. 2000; 48: 919–922.
29. Cohen R, Neuzillet C, Tijeras-Raballand A, et al. Targeting cancer cell metabolism in pancreatic adenocarcinoma. Oncotarget. 2015; 6: 16832–47.
30. Bristow RG, Hill RP. Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability. Nat Rev Cancer. 2008; 8: 180–92.
31. Semenza GL. Cancer-stromal cell interactions mediated by hypoxia-inducible factors promote angiogenesis, lymphangiogenesis, and metastasis. Oncogene. 2013; 32: 4057–63.
32. Yu M, Zhou Q, Zhou Y, et al. Metabolic phenotypes in pancreatic cancer. PLoS One. 2015; 10: e0115153.
33. Jones S, Zhang X, Parsons DW, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008; 321: 1801–6.
34. Hong SM, Park JY, Hruban RH, et al. Molecular signatures of pancreatic cancer. Arch Pathol Lab Med. 2011; 135: 716–27.
35. Bianco R, Melisi D, Ciardiello F, et al. Key cancer cell signal transduction pathways as therapeutic targets. Eur J Cancer. 2006; 42: 290–4.