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Expression by the Epidermal Growth Factor/Phosphatidylinositol 3-Kinase/PTEN/AKT/FRAP Pathway in Human Prostate Cancer Cells: Implications for Tumor Angiogenesis and Therapeutics1
The Johns Hopkins Oncology Center, Brady Urological Institute [H. Z., C. H., J. W. S.] and Departments of Pediatrics and Medicine and Institute of Genetic Medicine [K. C., D. F., E. L., G. L. S.], The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, and Laboratory of Molecular Oncology, The Rockefeller University, New York, New York 10021 [M-M. G.]
Dysregulated signal transduction from receptor tyrosine kinases to
phosphatidylinositol 3-kinase (PI3K), AKT (protein kinase B), and its
effector FKBP-rapamycin-associated protein (FRAP) occurs via autocrine
stimulation or inactivation of the tumor suppressor PTEN in many
cancers. Here we demonstrate that in human prostate cancer cells,
basal-, growth factor-, and mitogen-induced expression of
hypoxia-inducible factor 1 (HIF-1) 
, the regulated subunit of the
transcription factor HIF-1, is blocked by LY294002 and rapamycin,
inhibitors of PI3K and FRAP, respectively. HIF-1-dependent gene
transcription is blocked by dominant-negative AKT or PI3K and by
wild-type PTEN, whereas transcription is stimulated by constitutively
active AKT or dominant-negative PTEN. LY294002 and rapamycin also
inhibit growth factor- and mitogen-induced secretion of vascular
endothelial growth factor, the product of a known HIF-1 target gene,
thus linking the PI3K/PTEN/AKT/FRAP pathway, HIF-1, and tumor
angiogenesis. These data indicate that pharmacological agents that
target PI3K, AKT, or FRAP in tumor cells inhibit HIF-1 expression
and that such inhibition may contribute to therapeutic efficacy.
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 B. N. Gomperts and R. M. Strieter CXC Chemokines in Angiogenesis and Metastases Am. Assoc. Cancer Res. Educ. Book, April 1, 2006; 2006(1): 11 - 18. [Full Text] [PDF]
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M. Calvani, A. Rapisarda, B. Uranchimeg, R. H. Shoemaker, and G. Melillo Hypoxic induction of an HIF-1{alpha}-dependent bFGF autocrine loop drives angiogenesis in human endothelial cells Blood, April 1, 2006; 107(7): 2705 - 2712. [Abstract] [Full Text] [PDF]
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N. Pore, Z. Jiang, A. Gupta, G. Cerniglia, G. D. Kao, and A. Maity EGFR Tyrosine Kinase Inhibitors Decrease VEGF Expression by Both Hypoxia-Inducible Factor (HIF)-1-Independent and HIF-1-Dependent Mechanisms. Cancer Res., March 15, 2006; 66(6): 3197 - 3204. [Abstract] [Full Text] [PDF]
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F. Kaper, N. Dornhoefer, and A. J. Giaccia Mutations in the PI3K/PTEN/TSC2 Pathway Contribute to Mammalian Target of Rapamycin Activity and Increased Translation under Hypoxic Conditions Cancer Res., February 1, 2006; 66(3): 1561 - 1569. [Abstract] [Full Text] [PDF]
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D. T. Dang, F. Chen, L. B. Gardner, J. M. Cummins, C. Rago, F. Bunz, S. V. Kantsevoy, and L. H. Dang Hypoxia-Inducible Factor-1{alpha} Promotes Nonhypoxia-Mediated Proliferation in Colon Cancer Cells and Xenografts Cancer Res., February 1, 2006; 66(3): 1684 - 1693. [Abstract] [Full Text] [PDF]
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N. Skuli, S. Monferran, C. Delmas, I. Lajoie-Mazenc, G. Favre, C. Toulas, and E. Cohen-Jonathan-Moyal Activation of RhoB by Hypoxia Controls Hypoxia-Inducible Factor-1{alpha} Stabilization through Glycogen Synthase Kinase-3 in U87 Glioblastoma Cells Cancer Res., January 1, 2006; 66(1): 482 - 489. [Abstract] [Full Text] [PDF]
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 H. Acker The oxygen sensing signal cascade under the influence of reactive oxygen species Phil Trans R Soc B, December 29, 2005; 360(1464): 2201 - 2210. [Abstract] [Full Text] [PDF]
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 A. Dekanty, S. Lavista-Llanos, M. Irisarri, S. Oldham, and P. Wappner The insulin-PI3K/TOR pathway induces a HIF-dependent transcriptional response in Drosophila by promoting nuclear localization of HIF-{alpha}/Sima J. Cell Sci., December 1, 2005; 118(23): 5431 - 5441. [Abstract] [Full Text] [PDF]
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 K. S. Lee, H. S. Park, S. J. Park, S. R. Kim, K. H. Min, S. M. Jin, K.-H. Park, U.-H. Kim, C. Y. Kim, and Y. C. Lee A Prodrug of Cysteine, L-2-Oxothiazolidine-4-carboxylic Acid, Regulates Vascular Permeability by Reducing Vascular Endothelial Growth Factor Expression in Asthma Mol. Pharmacol., November 1, 2005; 68(5): 1281 - 1290. [Abstract] [Full Text] [PDF]
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R. H. Wenger, D. P. Stiehl, and G. Camenisch Integration of Oxygen Signaling at the Consensus HRE Sci. Signal., October 18, 2005; 2005(306): re12 - re12. [Abstract] [Full Text] [PDF]
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D. Kong, E. J. Park, A. G. Stephen, M. Calvani, J. H. Cardellina, A. Monks, R. J. Fisher, R. H. Shoemaker, and G. Melillo Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity Cancer Res., October 1, 2005; 65(19): 9047 - 9055. [Abstract] [Full Text] [PDF]
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Q. Zhang, X. Tang, Q. Y. Lu, Z. F. Zhang, J. Brown, and A. D. Le Resveratrol inhibits hypoxia-induced accumulation of hypoxia-inducible factor-1{alpha} and VEGF expression in human tongue squamous cell carcinoma and hepatoma cells Mol. Cancer Ther., October 1, 2005; 4(10): 1465 - 1474. [Abstract] [Full Text] [PDF]
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Y.-T. Huang, S.-L. Pan, J.-H. Guh, Y.-L. Chang, F.-Y. Lee, S.-C. Kuo, and C.-M. Teng YC-1 suppresses constitutive nuclear factor-{kappa}B activation and induces apoptosis in human prostate cancer cells Mol. Cancer Ther., October 1, 2005; 4(10): 1628 - 1635. [Abstract] [Full Text] [PDF]
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 A. Maloyan, L. Eli-Berchoer, G. L. Semenza, G. Gerstenblith, M. D. Stern, and M. Horowitz HIF-1{alpha}-targeted pathways are activated by heat acclimation and contribute to acclimation-ischemic cross-tolerance in the heart Physiol Genomics, September 21, 2005; 23(1): 79 - 88. [Abstract] [Full Text] [PDF]
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J.-Y. Han, S. H. Oh, F. Morgillo, J. N. Myers, E. Kim, W. K. Hong, and H.-Y. Lee Hypoxia-inducible Factor 1{alpha} and Antiangiogenic Activity of Farnesyltransferase Inhibitor SCH66336 in Human Aerodigestive Tract Cancer J Natl Cancer Inst, September 7, 2005; 97(17): 1272 - 1286. [Abstract] [Full Text] [PDF]
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D. Trisciuoglio, A. Iervolino, G. Zupi, and D. Del Bufalo Involvement of PI3K and MAPK Signaling in bcl-2-induced Vascular Endothelial Growth Factor Expression in Melanoma Cells Mol. Biol. Cell, September 1, 2005; 16(9): 4153 - 4162. [Abstract] [Full Text] [PDF]
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 A. A. Adjei and M. Hidalgo Intracellular Signal Transduction Pathway Proteins As Targets for Cancer Therapy J. Clin. Oncol., August 10, 2005; 23(23): 5386 - 5403. [Abstract] [Full Text] [PDF]
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D. W. Nelson, H. Cao, Y. Zhu, B. Sunar-Reeder, C. Y.H. Choi, J. D. Faix, J. M. Brown, A. C. Koong, A. J. Giaccia, and Q.-T. Le A Noninvasive Approach for Assessing Tumor Hypoxia in Xenografts: Developing a Urinary Marker for Hypoxia Cancer Res., July 15, 2005; 65(14): 6151 - 6158. [Abstract] [Full Text] [PDF]
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 R. Busca, E. Berra, C. Gaggioli, M. Khaled, K. Bille, B. Marchetti, R. Thyss, G. Fitsialos, L. Larribere, C. Bertolotto, et al. Hypoxia-inducible factor 1{alpha} is a new target of microphthalmia-associated transcription factor (MITF) in melanoma cells J. Cell Biol., July 4, 2005; 170(1): 49 - 59. [Abstract] [Full Text] [PDF]
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 T Gaber, R Dziurla, R Tripmacher, G R Burmester, and F Buttgereit Hypoxia inducible factor (HIF) in rheumatology: low O2! See what HIF can do! Ann Rheum Dis, July 1, 2005; 64(7): 971 - 980. [Abstract] [Full Text] [PDF]
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B. M. Emerling, L. C. Platanias, E. Black, A. R. Nebreda, R. J. Davis, and N. S. Chandel Mitochondrial Reactive Oxygen Species Activation of p38 Mitogen-Activated Protein Kinase Is Required for Hypoxia Signaling Mol. Cell. Biol., June 15, 2005; 25(12): 4853 - 4862. [Abstract] [Full Text] [PDF]
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A. Xiao, C. Yin, C. Yang, A. Di Cristofano, P. P. Pandolfi, and T. Van Dyke Somatic Induction of Pten Loss in a Preclinical Astrocytoma Model Reveals Major Roles in Disease Progression and Avenues for Target Discovery and Validation Cancer Res., June 15, 2005; 65(12): 5172 - 5180. [Abstract] [Full Text] [PDF]
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 H. Nakamura, Y. Makino, K. Okamoto, L. Poellinger, K. Ohnuma, C. Morimoto, and H. Tanaka TCR Engagement Increases Hypoxia-Inducible Factor-1{alpha} Protein Synthesis via Rapamycin-Sensitive Pathway under Hypoxic Conditions in Human Peripheral T Cells J. Immunol., June 15, 2005; 174(12): 7592 - 7599. [Abstract] [Full Text] [PDF]
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R. J. Phillips, J. Mestas, M. Gharaee-Kermani, M. D. Burdick, A. Sica, J. A. Belperio, M. P. Keane, and R. M. Strieter Epidermal Growth Factor and Hypoxia-induced Expression of CXC Chemokine Receptor 4 on Non-small Cell Lung Cancer Cells Is Regulated by the Phosphatidylinositol 3-Kinase/PTEN/AKT/Mammalian Target of Rapamycin Signaling Pathway and Activation of Hypoxia Inducible Factor-1{alpha} J. Biol. Chem., June 10, 2005; 280(23): 22473 - 22481. [Abstract] [Full Text] [PDF]
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 G. W. Cole Jr, A. M. Alleva, R. M. Reddy, J. B. Maxhimer, J. Zuo, D. S. Schrump, and D. M. Nguyen The selective epidermal growth factor receptor tyrosine kinase inhibitor PD153035 suppresses expression of prometastasis phenotypes in malignant pleural mesothelioma cells in vitro J. Thorac. Cardiovasc. Surg., May 1, 2005; 129(5): 1010 - 1017. [Abstract] [Full Text] [PDF]
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C. Treins, S. Giorgetti-Peraldi, J. Murdaca, M.-N. Monthouel-Kartmann, and E. Van Obberghen Regulation of Hypoxia-Inducible Factor (HIF)-1 Activity and Expression of HIF Hydroxylases in Response to Insulin-Like Growth Factor I Mol. Endocrinol., May 1, 2005; 19(5): 1304 - 1317. [Abstract] [Full Text] [PDF]
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K. M. Connor, S. Subbaram, K. J. Regan, K. K. Nelson, J. E. Mazurkiewicz, P. J. Bartholomew, A. E. Aplin, Y.-T. Tai, J. Aguirre-Ghiso, S. C. Flores, et al. Mitochondrial H2O2 Regulates the Angiogenic Phenotype via PTEN Oxidation J. Biol. Chem., April 29, 2005; 280(17): 16916 - 16924. [Abstract] [Full Text] [PDF]
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Y. M. Li, B. P. Zhou, J. Deng, Y. Pan, N. Hay, and M.-C. Hung A Hypoxia-Independent Hypoxia-Inducible Factor-1 Activation Pathway Induced by Phosphatidylinositol-3 Kinase/Akt in HER2 Overexpressing Cells Cancer Res., April 15, 2005; 65(8): 3257 - 3263. [Abstract] [Full Text] [PDF]
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G. J. Kelloff, J. M. Hoffman, B. Johnson, H. I. Scher, B. A. Siegel, E. Y. Cheng, B. D. Cheson, J. O'Shaughnessy, K. Z. Guyton, D. A. Mankoff, et al. Progress and Promise of FDG-PET Imaging for Cancer Patient Management and Oncologic Drug Development Clin. Cancer Res., April 15, 2005; 11(8): 2785 - 2808. [Abstract] [Full Text] [PDF]
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