Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer

Thomas, George V.; Tran, Chris; Mellinghoff, Ingo K.; Welsbie, Derek S.; Chan, Eric J.; Fueger, Barbara J.; Czernin, Johannes; Sawyers, Charles L.

doi:10.1038/nm1337

Cited by 573 publications

(415 citation statements)

References 20 publications

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“…Indeed, we determined by quantitative RT-PCR that PTND111-136 significantly down-regulated the expression of genes involved in hypoxia and the angiogenesis pathway such as VEGF-A as suggested previously (38). Moreover, further experiments are warranted to explain these results and more particularly to explore the role of PTND111-136 in phosphoinositide 3-kinase/Akt/mammalian target of rapamycin signaling, because the expression of HIF-1a and VEGF-A was recently shown to be dependent on the mammalian target of rapamycin pathway (39,40).…”

Section: Discussionmentioning

confidence: 55%

16-kDa fragment of pleiotrophin acts on endothelial and breast tumor cells and inhibits tumor development

Ducès

Karaky

Martel-Renoir

et al. 2008

Molecular Cancer Therapeutics

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Pleiotrophin (PTN) is a 136-amino acid secreted heparinbinding protein that is considered as a rate-limiting growth and an angiogenic factor in the onset, invasion, and metastatic process of many tumors. Its mitogenic and tumorigenic activities are mediated by the COOH-terminal residues 111 to 136 of PTN, allowing it to bind to cell surface tyrosine kinase-linked receptors. We investigated a new strategy consisting in evaluating the antitumor effect of a truncated PTN, lacking the COOH-terminal 111 to 136 portion of the molecule (PTN#111-136), which may act as a dominant-negative effector for its mitogenic, angiogenic, and tumorigenic activities by heterodimerizing with the wild-type protein. In vitro studies showed that PTN#111-136 selectively inhibited a PTN-dependent MDA-MB-231 breast tumor and endothelial cell proliferation and that, in MDA-MB-231 cells expressing PTN#111-136, the vascular endothelial growth factor-A and hypoxia-inducible factor-1A mRNA levels were significantly decreased by 59% and 71%, respectively, compared with levels in wild-type cells. In vivo, intramuscular electrotransfer of a plasmid encoding a secretable form of PTN#111-136 was shown to inhibit MDA-MB-231 tumor growth by 81%. This antitumor effect was associated with the detection of the PTN#111-136 molecule in the muscle and tumor extracts, the suppression of neovascularization within the tumors, and a decline in the Ki-67 proliferative index. Because PTN is rarely found in normal tissue, our data show that targeted PTN may represent an attractive and new therapeutic approach to the fight against cancer.

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Section: Discussionmentioning

confidence: 55%

16-kDa fragment of pleiotrophin acts on endothelial and breast tumor cells and inhibits tumor development

Ducès

Karaky

Martel-Renoir

et al. 2008

Molecular Cancer Therapeutics

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“…Several studies have suggested that the mTOR inhibitor rapamycin can decrease HIF-1a expression (18,21,(38)(39)(40). However, we found that treatment of U87MG cells with 10 nmol/L of the drug had no effect on HIF-1a expression in response to either CoCl 2 or hypoxia (Fig.…”

Section: Resultsmentioning

confidence: 65%

Akt1 Activation Can Augment Hypoxia-Inducible Factor-1α Expression by Increasing Protein Translation through a Mammalian Target of Rapamycin–Independent Pathway

Pore

Jiang

Shu

et al. 2006

Molecular Cancer Research

172

134

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The phosphoinositide 3-kinase (PI3K)/Akt pathway is commonly activated in cancer; therefore, we investigated its role in hypoxia-inducible factor-1A (HIF-1A) regulation. Inhibition of PI3K in U87MG glioblastoma cells, which have activated PI3K/Akt activity secondary to phosphatase and tensin homologue deleted on chromosome 10 (PTEN) mutation, with LY294002 blunted the induction of HIF-1A protein and its targets vascular endothelial growth factor and glut1 mRNA in response to hypoxia. Introduction of wild-type PTEN into these cells also blunted HIF-1A induction in response to hypoxia and decreased HIF-1A accumulation in the presence of the proteasomal inhibitor MG132. Akt small interfering RNA (siRNA) also decreased HIF-1A induction under hypoxia and its accumulation in normoxia in the presence of dimethyloxallyl glycine, a prolyl hydroxylase inhibitor that prevents HIF-1A degradation. Metabolic labeling studies showed that Akt siRNA decreased HIF-1A translation in normoxia in the presence of dimethyloxallyl glycine and in hypoxia. Inhibition of mammalian target of rapamycin (mTOR) with rapamycin (10-100 nmol/L) had no significant effect on HIF-1A induction in a variety of cell lines, a finding that was confirmed using mTOR siRNA. Furthermore, neither mTOR siRNA nor rapamycin decreased HIF-1A translation as determined by metabolic labeling studies. Therefore, our results indicate that Akt can augment HIF-1A expression by increasing its translation under both normoxic and hypoxic conditions; however, the pathway we are investigating seems to be rapamycin insensitive and mTOR independent. These observations, which were made on cells grown in standard tissue culture medium (10% serum), were confirmed in PC3 prostate carcinoma cells. We did find that rapamycin could decrease HIF-1A expression when cells were cultured in low serum, but this seems to represent a different pathway. (Mol Cancer Res 2006;4(7):471 -9)

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“…Therefore, cellular changes, such as loss of intercellular junctions and epithelial de-differentiation involving HIFdependent as well as HIF-independent molecular pathways 48,[106][107][108] in addition to HIF-dependent and -independent alterations in p53 or NF-kB activity, 34,35,49,51 HGF signaling, 45,50,109 and modifications in ECM turnover and re-modeling [42][43][44][45][46][47] create the molecular environment for the development CC-RCC, which most likely requires additional genetic events. The importance of HIF activation in CC-RCC pathogenesis and growth is furthermore underscored by experimental and clinical studies, which demonstrated that inhibition of HIF-a translation by pharmacological targeting of mTOR correlated with reduced tumor growth, 110 and that increased expression of certain HIF target genes, such as CXCR4, as well as E-cadherin suppression was associated with disease progression. 111,112 With regard to the contribution of individual HIF-a homologs to renal tumor development, it is of interest that a substantial number of VHL-defective CC-RCC cell lines do not express HIF-1a, but express HIF-2a.…”

Section: Pvhl and Renal Cell Cancermentioning

confidence: 99%

The VHL tumor suppressor and HIF: insights from genetic studies in mice

2008

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The von Hippel-Lindau tumor suppressor gene product, pVHL, functions as the substrate recognition component of an E3-ubiquitin ligase, which targets the oxygen-sensitive a-subunit of hypoxia-inducible factor (HIF) for rapid proteasomal degradation under normoxic conditions and as such plays a central role in molecular oxygen sensing. Mutations in pVHL can be found in familial and sporadic clear cell carcinomas of the kidney, hemangioblastomas of the retina and central nervous system, and pheochromocytomas, underscoring its gatekeeper function in the pathogenesis of these tumors. Tissue-specific gene targeting of VHL in mice has demonstrated that efficient execution of pVHL-mediated HIF proteolysis under normoxia is fundamentally important for survival, proliferation, differentiation and normal physiology of many cell types, and has provided novel insights into the biological function of individual HIF transcription factors. In this review, we discuss the role of HIF in the development of the VHL phenotype. Germ-line mutations in the von Hippel-Lindau tumor (VHL) suppressor can be found in patients with VHL disease, a rare familial tumor syndrome characterized by the development of highly vascularized tumors in multiple organs. Major clinical manifestations of VHL disease include hemangioblastomas of the retina and central nervous system (CNS), renal cysts and renal cell carcinoma of the clear cell type (CC-RCC), pancreatic cysts and tumors, as well as pheochromocytomas. 1 The VHL tumor suppressor is also mutated in the majority of sporadic CC-RCCs, 2 highlighting its critical and central role in the regulation of cell growth and differentiation of epithelial kidney cells. Although the molecular function of the VHL gene product, pVHL, was initially not known when it was first identified by positional cloning in 1993, 3 observations that oxygen-dependent regulation of hypoxia-inducible genes was lost in VHL-deficient cell lines suggested a role for pVHL in oxygen sensing. [4][5][6] In a seminal paper, Maxwell et al. 7 showed that pVHL was critical for targeting the a-subunit of hypoxia-inducible factor (HIF) for oxygen-dependent proteolysis, thus providing a direct molecular link between VHLassociated tumorigenesis and oxygen sensing via HIF. HIFs belong to the PAS (Per-arylhydrocarbon receptor nuclear translocator (ARNT)-Sim) family of basic helix-loop-helix (bHLH) transcription factors and bind DNA as heterodimers. They consist of an oxygen-sensitive a-subunit and a constitutively expressed b-subunit, also known as ARNT or HIF-b. pVHL associates with the elongins B and C, cullin2 and Rbx [8][9][10][11][12] and functions as the substrate recognition component of an E3-ubiquitin ligase that ubiquitylates HIF-a. [13][14][15][16][17][18][19] All three HIF a-subunits, HIF-1a, HIF-2a and HIF-3a interact with pVHL. 7,20 This pVHL-HIF-a interaction is highly conserved between species, requires iron-and oxygen-dependent hydroxylation of specific proline residues (Pro402 and Pro564 in human HIF-1a; Pro405 and Pro531 in ...

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Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer

Cited by 573 publications

References 20 publications

16-kDa fragment of pleiotrophin acts on endothelial and breast tumor cells and inhibits tumor development

16-kDa fragment of pleiotrophin acts on endothelial and breast tumor cells and inhibits tumor development

Akt1 Activation Can Augment Hypoxia-Inducible Factor-1α Expression by Increasing Protein Translation through a Mammalian Target of Rapamycin–Independent Pathway

The VHL tumor suppressor and HIF: insights from genetic studies in mice

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