Open AccessJournal Article
Modulation of Hypoxia-inducible Factor 1α Expression by the Epidermal Growth Factor/Phosphatidylinositol 3-Kinase/PTEN/AKT/FRAP Pathway in Human Prostate Cancer Cells: Implications for Tumor Angiogenesis and Therapeutics
Hua Zhong,Kelly Chiles,David M. Feldser,Erik Laughner,Colleen Hanrahan,Maria Magdalena Georgescu,Jonathan W. Simons,Gregg L. Semenza +7 more
TLDR
It is demonstrated that in human prostate cancer cells, basal-, growth factor- and mitogen-induced expression of hypoxia-inducible factor 1 (HIF-1) alpha, the regulated subunit of the transcription factor Hif-1, is blocked by LY294002 and rapamycin, inhibitors of PI3K and FRAP, respectively.Abstract:
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) alpha, 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-1alpha expression and that such inhibition may contribute to therapeutic efficacy.read more
Citations
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Journal ArticleDOI
Targeting HIF-1 for cancer therapy
TL;DR: Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that are involved in crucial aspects of cancer biology, including angiogenesis, cell survival, glucose metabolism and invasion.
Journal ArticleDOI
Hypoxia — a key regulatory factor in tumour growth
TL;DR: Cells undergo a variety of biological responses when placed in hypoxic conditions, including activation of signalling pathways that regulate proliferation, angiogenesis and death, and many elements of the hypoxia-response pathway are good candidates for therapeutic targeting.
Journal ArticleDOI
Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor
Markus Guba,Philipp von Breitenbuch,Markus Steinbauer,Gudrun E. Koehl,Stefanie Flegel,Matthias Hornung,Christiane J. Bruns,Carl Zuelke,Stefan Farkas,Matthias Anthuber,Karl-Walter Jauch,Edward K Geissler +11 more
TL;DR: The use of RAPA, instead of cyclosporine, may reduce the chance of recurrent or de novo cancer in high-risk transplant patients and show antiangiogenic activities linked to a decrease in production of vascular endothelial growth factor and to a markedly inhibited response ofascular endothelial cells to stimulation by VEGF.
Journal ArticleDOI
The protein kinase B/Akt signalling pathway in human malignancy.
TL;DR: Recent developments in understanding the mechanisms and consequences of PKB/Akt activation in human malignancy are surveyed.
Journal ArticleDOI
Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics
TL;DR: This review summarizes the current state of knowledge regarding the molecular mechanisms by which Hif-1 contributes to cancer progression, focusing on clinical data associating increased HIF-1 levels with patient mortality and pharmacological data showing anticancer effects of H IF-1 inhibitors in mouse models of human cancer.
References
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Journal ArticleDOI
PTEN, a Putative Protein Tyrosine Phosphatase Gene Mutated in Human Brain, Breast, and Prostate Cancer
Jing Li,Clifford Yen,Danny Liaw,Katrina Podsypanina,Shikha Bose,Steven I. Wang,Janusz Puc,Christa Miliaresis,Linda Rodgers,Richard W. McCombie,Sandra H. Bigner,Beppino C. Giovanella,Michael Ittmann,B. Tycko,Hanina Hibshoosh,Michael Wigler,Ramon Parsons +16 more
TL;DR: The PTEN product has a protein tyrosine phosphatase domain and extensive homology to tensin, a protein that interacts with actin filaments at focal adhesions as discussed by the authors.
Journal ArticleDOI
The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis
Patrick H. Maxwell,Michael S. Wiesener,Gin-Wen Chang,Steven C. Clifford,Emma C. Vaux,Matthew Edward Cockman,Charles C. Wykoff,Christopher W. Pugh,Eamonn R. Maher,Peter J. Ratcliffe,Peter J. Ratcliffe +10 more
TL;DR: It is indicated that the interaction between HIF-1 and pVHL is iron dependent, and that it is necessary for the oxygen-dependent degradation of HIF α-subunits, which may underlie the angiogenic phenotype of VHL-associated tumours.
Journal Article
Overexpression of Hypoxia-inducible Factor 1α in Common Human Cancers and Their Metastases
Hua Zhong,Angelo M. De Marzo,Erik Laughner,Michael Lim,David A Hilton,David Zagzag,Peter Buechler,William B. Isaacs,Gregg L. Semenza,Jonathan W. Simons +9 more
TL;DR: The first clinical data indicating that HIF-1alpha may play an important role in human cancer progression are provided, indicating adaptations to a hypoxic microenvironment that are correlated with tumor invasion, metastasis, and lethality.
Journal ArticleDOI
The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase
Thomas F. Franke,Sung-Il Yang,Tung O. Chan,Ketaki Datta,Andrius Kazlauskas,Deborah K. Morrison,David R. Kaplan,Philip N. Tsichlis +7 more
TL;DR: It is shown that Akt and the Akt-related kinase AKT2 are activated by PDGF, and it is suggested that the AkT PH domain may be a mediator of PI 3-kinase signaling.
Journal ArticleDOI
New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway
TL;DR: A series of publications over the past year now suggest a mechanism by which PTEN loss of function results in tumors, and PTEN appears to negatively control the phosphoinositide 3-kinase signaling pathway for regulation of cell growth and survival by dephosphorylating the 3 position ofosphoinositides.