Effects of HIF-1 and HIF2 on Growth and Metabolism of Clear-Cell Renal Cell Carcinoma 786-0 Xenografts

Biswas, Swethajit; Troy, Helen; Leek, Russell; Chung, Yuen‐Li; Li, Jiliang; Raval, Raju R.; Turley, Helen; Gatter, Kevin C.; Griffiths, John R.; Stubbs, Marion; Harris, Adrian L.

doi:10.1155/2010/757908

Cited by 79 publications

(68 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…5C). Despite some overlapping effects, it has been reported that HIF-1␣ and HIF-2␣ regulate distinct genes (7,32). For example, HIF-1␣ is primarily involved in glucose metabolism, including upregulation of glycolytic enzymes and downregulation of electron transport chain activity (7).…”

Section: Discussionmentioning

confidence: 99%

Sunitinib induces apoptosis in pheochromocytoma tumor cells by inhibiting VEGFR2/Akt/mTOR/S6K1 pathways through modulation of Bcl-2 and BAD

Saito¹,

Tanaka²,

Aita³

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

Sunitinib is an oral multitargeted receptor tyrosine kinase inhibitor with antiangiogenic and antitumor activity that mainly targets vascular endothelial growth factor receptors (VEGFRs). Very recently, sunitinib has been shown to be an active agent for the treatment of malignant pheochromocytomas. However, it is unclear whether sunitinib acts only through an antiangiogenic mechanism or whether it may also directly target tumor cells. Sunitinib markedly induced apoptosis of PC12 cells in a dose-dependent and time-dependent manner. Furthermore, in support of these findings, we found that sunitinib induced a reduction in the expression of the antiapoptotic molecule Bcl-2 as well as dephosphorylation of the proapoptotic molecule BAD, which results in the activation of BAD in these cells. Consistent with these apoptotic effects, our results showed that sunitinib inhibited phosphorylation of Akt and mTOR and was followed by a reduction of S6K1, which is a well-known target of mTOR. Knockdown of VEGFR-2 attenuated the sunitinib-induced effects, including apoptosis and inhibition of signaling pathways such as the phosphorylation of Akt as well as mTOR, and Bcl-2, which confirmed that these effects could be mediated by VEGFR-2. In addition, silencing of S6K1 induced apoptosis accompanied by a decrease in the phosphorylation of BAD and Bcl-2, similar to that observed with sunitinib treatment. Thus, these results together suggest that sunitinib initially exerts its apoptotic effect through the inhibition of VEGFR-2, which, when followed by reduction of its downstream effectors, including Akt/mTOR/S6K1, may lead to inhibition of the antiapoptotic molecule Bcl-2 and activation of the proapoptotic molecule BAD in PC12 cells. However, PC12 cells do not precisely reflect the pathogenesis of malignant cells. Therefore, we confirmed the key findings by replicating these experiments in human neuroblastoma SK-N-SH cells.

show abstract

Section: Discussionmentioning

confidence: 99%

Sunitinib induces apoptosis in pheochromocytoma tumor cells by inhibiting VEGFR2/Akt/mTOR/S6K1 pathways through modulation of Bcl-2 and BAD

Saito¹,

Tanaka²,

Aita³

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

show abstract

“…30 Interestingly, HIF2α-xenografts demonstrate elevated expression of key mitochondrial proteins, such as pyruvate dehydrogenase (PDH, catalyzing the first step of the Krebs cycle) and TOMM20, the decreased expression of the Krebs cycle inhibitor pyruvate dehydrogenase kinase (PDK1), and decreased intra-tumoral lactate levels, indicating that HIF2α-tumors rely less on glycolysis and more on oxidative metabolism. 30 Conversely, HIF1α-xenografts demonstrated elevated expression of PDK1 and the mitophagy marker BNIP3, suggesting that HIF1α in renal cancer cells functions as a tumor suppressor and promotes autophagic cell death. 30 HIF2α in epithelial cancer cells plays an important role in the pathogenesis and prognosis of some type of cancers.…”

Section: Discussionmentioning

confidence: 99%

Metabolic reprogramming and two-compartment tumor metabolism

et al. 2012

View full text Add to dashboard Cite

“…VHL encodes an E3 ubiquitin ligase ( 12,13 ) that targets HIF1α ( HIF1A ) and HIF2α ( EPAS1 ) for degradation ( 14,15 ). VHL loss in ccRCC results in constitutive activation of HIF1/2α and subsequent transactivation ( 16,17 ) of downstream genes regulating angiogenesis, glycolysis ( 18 ), lipogenesis ( 19,20 ), cell cycle ( 21 ), and antiapoptosis ( 22 ).…”

mentioning

confidence: 99%

VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma

et al. 2017

View full text Add to dashboard Cite

Protein-coding mutations in clear cell renal cell carcinoma (ccRCC) have been extensively characterized, frequently involving inactivation of the von Hippel-Lindau ( VHL ) tumor suppressor. Roles for noncoding cis -regulatory aberrations in ccRCC tumorigenesis, however, remain unclear. Analyzing 10 primary tumor/normal pairs and 9 cell lines across 79 chromatin profi les, we observed pervasive enhancer malfunction in ccRCC, with cognate enhancer-target genes associated with tissue-specifi c aspects of malignancy. Superenhancer profi ling identifi ed ZNF395 as a ccRCCspecifi c and VHL-regulated master regulator whose depletion causes near-complete tumor elimination in vitro and in vivo . VHL loss predominantly drives enhancer/superenhancer deregulation more so than promoters, with acquisition of active enhancer marks (H3K27ac, H3K4me1) near ccRCC hallmark genes. Mechanistically, VHL loss stabilizes HIF2α-HIF1β heterodimer binding at enhancers, subsequently recruiting histone acetyltransferase p300 without overtly affecting preexisting promoter-enhancer interactions. Subtype-specifi c driver mutations such as VHL may thus propagate unique pathogenic dependencies in ccRCC by modulating epigenomic landscapes and cancer gene expression. SIGnIFICAnCE:Comprehensive epigenomic profi ling of ccRCC establishes a compendium of somatically altered cis -regulatory elements, uncovering new potential targets including ZNF395, a ccRCC master regulator. Loss of VHL , a ccRCC signature event, causes pervasive enhancer malfunction, with binding of enhancer-centric HIF2α and recruitment of histone acetyltransferase p300 at preexisting lineage-specifi c promoter-enhancer complexes. Cancer Discov; 7(11); 1284-305.

show abstract

Effects of HIF-1 and HIF2 on Growth and Metabolism of Clear-Cell Renal Cell Carcinoma 786-0 Xenografts

Cited by 79 publications

References 46 publications

Sunitinib induces apoptosis in pheochromocytoma tumor cells by inhibiting VEGFR2/Akt/mTOR/S6K1 pathways through modulation of Bcl-2 and BAD

Sunitinib induces apoptosis in pheochromocytoma tumor cells by inhibiting VEGFR2/Akt/mTOR/S6K1 pathways through modulation of Bcl-2 and BAD

Metabolic reprogramming and two-compartment tumor metabolism

VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma

Contact Info

Product

Resources

About