Chronic hypoxia promotes an aggressive phenotype in rat prostate cancer cells

Alqawi, Omar; Wang, Hong P.; Espiritu, Myrna; Singh, Gurmit

doi:10.1080/10715760701361531

Cited by 36 publications

(26 citation statements)

References 41 publications

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“…On the other hand, there are clones within the tumor that react to hypoxic stress with adaptive processes that, through modification of gene expression, confer an aggressive phenotype, promoting local and distant spread (Fig. 4A, B) [8][9][10][11][12].…”

Section: Fallsmentioning

confidence: 99%

Hypoxia and Aggressive Tumor Phenotype: Implications for Therapy and Prognosis

2008

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Tumor hypoxia, mostly resulting from poor perfusion and anemia, is one of the key factors in inducing the development of cell clones with an aggressive and treatment-resistant phenotype that leads to rapid progression and poor prognosis. Studies in patients with solid tumors suggest that there is a range of hemoglobin (Hb) concentrations that is optimum for tumor oxygenation. When used to achieve an Hb level within this range, erythropoiesis-stimulating agents (ESAs) can be expected to increase tumor oxygenation, and this may favorably influence sensitivity to treatment as well as quality of

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Section: Fallsmentioning

confidence: 99%

Hypoxia and Aggressive Tumor Phenotype: Implications for Therapy and Prognosis

2008

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“…5). For example, cells incubated under chronic hyp oxia for several weeks can have a higher invasive capacity than under acute hypoxia [2]. On the other hand, cells exposed to chronic hypoxia can be incapable of replication restart after reoxygenation and, therefore, should not contribute to continued tumorigenesis [61].…”

Section: Biological Consequencesmentioning

confidence: 99%

Acute versus chronic hypoxia in tumors

2012

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There are large variations in reported spontaneous fluctuations in acute hypoxia that are dependent on the cell lines investigated and the detection method used. In addition to differing hypoxia levels, exposure times used to induce in vitro and in vivo experimental acute and chronic hypoxia range from 30 min to several weeks with no clear boundaries separating the two. Evaluation of the biological consequences of each hypoxia subtype revealed a general trend that acute hypoxia leads to a more aggressive phenotype. Importantly, more information on the occurrence of acute and chronic hypoxia in human tumors is needed to help our understanding of the clinical consequences.

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“…Correlation between SENP1 and HIF1␣ in Human Prostate Cancer-Elevated HIF1␣ levels are commonly observed in human PCa and are associated with more aggressive forms of the carcinoma (14,21,22). Because our previous studies suggested that SENP1 stabilizes HIF1␣ in mouse embryonic fibroblast cells and the studies above presented a similar phenomenon in adult mice, we sought to determine whether the level of SENP1 correlates with the elevated levels of HIF1␣ in human PCa.…”

Section: Senp1 Transgenic Mice Enhance Angiogenesis Via Stabilizationmentioning

confidence: 99%

SENP1 Induces Prostatic Intraepithelial Neoplasia through Multiple Mechanisms

Bawa-Khalfe

Cheng

Lin

et al. 2010

Journal of Biological Chemistry

101

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SUMOylation has been shown to modulate DNA replication/ repair, cell cycle progression, signal transduction, and the hypoxic response. SUMO (small ubiquitin-like modifier)-specific proteases regulate SUMOylation, but how changes in the expression of these proteases contribute to physiological and/or pathophysiological events remains undefined. Here, we show that SENP1 (sentrin/SUMO-specific protease 1) is highly expressed in human prostate cancer specimens and correlates with hypoxia-inducing factor 1␣ (HIF1␣) expression. Mechanistic studies in a mouse model indicate that androgen-driven expression of murine SENP1 leads to HIF1␣ stabilization, enhanced vascular endothelial growth factor production, and angiogenesis. Further pathological assessment of the mouse indicates that SENP1 overexpression induces transformation of the normal prostate gland and gradually facilitates the onset of high-grade prostatic intraepithelial neoplasia. Consistent with cell culture studies, SENP1 enhances prostate epithelial cell proliferation via modulating the androgen receptor and cyclin D 1 . These results demonstrate that deSUMOylation plays a critical role in prostate pathogenesis through induction of HIF1␣-dependent angiogenesis and enhanced cell proliferation.SUMO (small ubiquitin-like modifier) modification of protein substrates is a dynamic process that modulates the target protein's expression, function, and/or subcellular location (1, 2). SUMOylation is regulated by SUMO-specific activating (E1), conjugating (E2), and ligating (E3) enzymes and reversed by a family of sentrin/SUMO-specific proteases (3-5). These enzymes are critical for maintaining a balance between the level of SUMOylated and unmodified cellular substrates and hence play an important role in mediating normal cellular physiology.Several large-scale gene expression studies report changes in the levels of SUMO E1, E2, and SENP1 (sentrin/SUMO-specific protease 1) in various cancers, suggesting an imbalance in the SUMO system (6 -9). SENP1 mRNA levels are elevated in thyroid oncocytic adenocarcinoma (6) and human prostate cancer (PCa) 3 (10). In addition, using in situ hybridization, we recently found greater SENP1 mRNA levels in precancerous prostatic intraepithelial neoplasia (PIN) compared with adjacent normal prostate epithelia (10). Transformation of the normal prostate epithelia to carcinoma is preceded by the development of this well characterized PIN state (11). The presence of elevated SENP1 levels in this precursor state posed the question as to whether SENP1 induction is not associated merely with the carcinoma but instead could directly contribute to prostate carcinogenesis.Recently, we demonstrated that SENP1 enhances the stability of hypoxia-inducing factor 1␣ (HIF1␣) and, consequently, HIF1␣-mediated transcription; in the absence of SENP1, HIF1␣ is actively SUMOylated and subsequently degraded under hypoxic conditions (12). In prostate carcinogenesis, hypoxic tissue environments emerge due to rapidly proliferating cancer cells, and HIF1␣ is post...

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Chronic hypoxia promotes an aggressive phenotype in rat prostate cancer cells

Cited by 36 publications

References 41 publications

Hypoxia and Aggressive Tumor Phenotype: Implications for Therapy and Prognosis

Hypoxia and Aggressive Tumor Phenotype: Implications for Therapy and Prognosis

Acute versus chronic hypoxia in tumors

SENP1 Induces Prostatic Intraepithelial Neoplasia through Multiple Mechanisms

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