Human hormone-refractory prostate cancers can harbor mutations in the O 2 -dependent degradation domain of hypoxia inducible factor-1α (HIF-1α)

Anastasiadis, Aristotelis G.; Ghafar, Mohamed A.; Salomon, Laurent; Vacherot, Francis; Benedit, Patricia; Chen, Min-Wei; Shabsigh, Ahmad; Burchardt, Martin; Chopin, Dominique; Shabsigh, Ridwan; Buttyan, Ralph

doi:10.1007/s00432-002-0346-1

Cited by 33 publications

(23 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The identification of mutations within the oxygen-dependent domain of HIF-1a was recently shown in a small number of prostate cancers (23,24). The presence of mutations implies that the activation of HIF-1a can be selected for enabling the expression of this protein under inappropriate conditions.…”

Section: Discussionmentioning

confidence: 99%

“…The current study confirms the expression of HIF-1a in prostate cancer and is the first to show the presence of HIF-2a expression. Furthermore, expression of both HIF-1a and HIF-2a were significantly correlated in neoplastic tissues, suggesting that both isoforms play a functional role in the tumor response to hypoxia and therefore play an important role in the development and progression of this disease.The identification of mutations within the oxygen-dependent domain of HIF-1a was recently shown in a small number of prostate cancers (23,24). The presence of mutations implies that the activation of HIF-1a can be selected for enabling the expression of this protein under inappropriate conditions.…”

mentioning

confidence: 99%

See 1 more Smart Citation

The Androgen Receptor Is Significantly Associated with Vascular Endothelial Growth Factor and Hypoxia Sensing via Hypoxia-Inducible Factors HIF-1a, HIF-2a, and the Prolyl Hydroxylases in Human Prostate Cancer

Boddy

Fox

Chen

et al. 2005

Clinical Cancer Research

149

132

View full text Add to dashboard Cite

Purpose: Hypoxia regulates key biological processes including angiogenesis via the transcription factor, hypoxia-inducible factor (HIF). In prostate cancer, angiogenesis is also influenced by androgens, and recent cell line studies suggest that this effect is partly mediated by HIF.The study aimed to assess whether a relationship exists in human prostate cancer between expression of the androgen receptor, HIFs, and the key angiogenesis factor, vascular endothelial growth factor (VEGF). Experimental Design: A tissue microarray comprised of 149 radical prostatectomy specimens was constructed. Semiquantitative immunohistochemical analysis was used to assess the expression of the androgen receptor, VEGF and HIF-1a and 2a, and their regulatory prolyl hydroxylase enzymes (PHD1, PHD2, and PHD3). Statistical analysis compared these factors with each other and with prostate-specific antigen relapse.Results: There was a significant correlation between HIF-1a and HIF-2a expression (P = 0.02), and with androgen receptor (P = 0.04 and P < 0.001, respectively) and VEGF expression (P = 0.05 and P <0.001, respectively).VEGF was also significantly related to the androgen receptor (P = 0.05), whereas PHD2 was inversely related to HIF-2a expression. No significant association was shown between HIF-1a or HIF-2a and time to prostate-specific antigen recurrence (P = 0.20 and P = 0.94, respectively). Conclusions: These findings confirm the relationship between hypoxia and the androgen receptor in prostate cancer, and show for the first time, the role of HIF-2a in this disease process. They provide clinical evidence to support the recent cell line findings that androgens may regulateVEGF levels through the activation of HIF in androgen-sensitive tumors. Inhibition of both the HIF pathways may provide new therapeutic options in the management of this disease.One of the key pathways involved in the response to hypoxia is the HIF-1 pathway. HIF-1 is an oxygen-dependent transcriptional activator which is composed of two basic helix-loop-helix PAS proteins, HIF-1a and HIF-1b (1). HIF1b (aryl hydrocarbon nuclear translocator) is constitutively expressed and largely unaffected by oxygen tension in contrast to HIF-1a, which is the responsive HIF-1 element (2). Although three a subunits have been identified, most of the studies to date have concentrated on the role of HIF-1a, with those of HIF-2a and HIF-3a remaining less clear (3).The level and activity of the HIF-1a subunit is tightly regulated through a number of posttranslational modifications. In the presence of oxygen, the prolyl hydroxylase enzymes (PHD1, PHD2, and PHD3) cause site-specific hydroxylation of two proline residues, P402 and P564, within the oxygen-dependent degradation domain of HIF-1a. This hydroxylation allows for the recognition of HIF-1a by the tumor suppressor von Hippel-Lindau protein, an E3 ubiquitin ligase complex, which targets HIF-1a for degradation (4). Hydroxylation of a conserved asparagine residue (Asp 803 ) within the caspase-activated DNase domain ...

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

The Androgen Receptor Is Significantly Associated with Vascular Endothelial Growth Factor and Hypoxia Sensing via Hypoxia-Inducible Factors HIF-1a, HIF-2a, and the Prolyl Hydroxylases in Human Prostate Cancer

Boddy

Fox

Chen

et al. 2005

Clinical Cancer Research

149

132

View full text Add to dashboard Cite

show abstract

“…The lack of significant associations of the HIF-1a P582S polymorphism with aggressive prostate cancer in our study is somewhat at odds given previous observations. We detected a somatic P582S mutation in an androgen-independent prostate cancer case with metastasis to the bone [13] as did another group in prostate tumor [14]. A case-control study observed higher frequencies of the P582S T-containing variant genotypes among 196 androgen-independent prostate cancer cases compared with 196 controls [15].…”

Section: Discussionmentioning

confidence: 51%

“…Interestingly, our group recently identified the P582S C!T as a somatic mutation in bone marrow metastatic biopsies from men with androgen-independent prostate cancers; and our in vitro experiment demonstrated that, under normoxic conditions, this mutation had significantly higher transcription activity, which reflected increased HIF-1a protein expression [13]. Another group also found the same somatic mutation in prostate tumors [14]. One clinical case-control study found that the P582S T-containing variant genotypes were more common among men with androgen-independent prostate cancer [15].…”

Section: Introductionmentioning

confidence: 53%

Energetic Systems and Nanotechnology - A Look Ahead

Kavetsky¹,

Anand²,

Goldwasser³

et al. 2005

View full text Add to dashboard Cite

Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE 06-02-20082. REPORT TYPE SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTThe P582S C->T and A588T G->A polymorphisms in the Hypoxia-inducible factor-1α (HIF-1α) gene have been associated with enhanced stability of the protein and androgen-independent prostate cancer (CaP) During the course of our research we published that P582S polymorphism was not associated with CaP (see appendix). However we observed a significant interaction of the P582S genotype with insulin-like growth factor binding protein (IGFBP)-3 in modifying CaP risk such that higher IGFBP-3 levels (>= versus

show abstract

“…44 However, the P582S polymorphism has been found to be associated with other disease phenotypes, including decreased coronary artery collateralization in ischemic heart disease patients, lower exercise-induced oxygen consumption in patients age 60 and older, prostate carcinoma, head and neck cancer and type 2 diabetes. [45][46][47][48][49][50] …”

Section: Chuvash Polycythemia and The P582s Polymorphism In Hif-1αmentioning

confidence: 99%

Oxygen Sensing: Recent Insights from Idiopathic Erythrocytosis

Lee

Percy²,

McMullin

2006

Cell Cycle

View full text Add to dashboard Cite

Human hormone-refractory prostate cancers can harbor mutations in the O 2 -dependent degradation domain of hypoxia inducible factor-1α (HIF-1α)

Cited by 33 publications

References 16 publications

The Androgen Receptor Is Significantly Associated with Vascular Endothelial Growth Factor and Hypoxia Sensing via Hypoxia-Inducible Factors HIF-1a, HIF-2a, and the Prolyl Hydroxylases in Human Prostate Cancer

The Androgen Receptor Is Significantly Associated with Vascular Endothelial Growth Factor and Hypoxia Sensing via Hypoxia-Inducible Factors HIF-1a, HIF-2a, and the Prolyl Hydroxylases in Human Prostate Cancer

Energetic Systems and Nanotechnology - A Look Ahead

Oxygen Sensing: Recent Insights from Idiopathic Erythrocytosis

Contact Info

Product

Resources

About