Castration Therapy of Prostate Cancer Results in Downregulation of HIF-1α Levels

Al-Ubaidi, Firas L. T.; Schultz, Niklas; Egevad, Lars; Granfors, Torvald; Helleday, Thomas

doi:10.1016/j.ijrobp.2011.10.038

Cited by 23 publications

(19 citation statements)

References 17 publications

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“…A more detailed understanding of the cellular and molecular mechanisms behind this synergism would allow us to optimize treatment and may also give rise to novel therapeutic applications. We have previously shown that the hypoxia levels in prostate cancer tissue decrease following castration (3). Because hypoxia is associated with poor response to radiotherapy (4,5), reduced hypoxia after castration may offer one plausible mechanistic explanation.…”

Section: Introductionmentioning

confidence: 97%

Castration Therapy Results in Decreased Ku70 Levels in Prostate Cancer

Al-Ubaidi

Schultz

Loseva

et al. 2013

Clinical Cancer Research

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Purpose: Neoadjuvant castration improves response to radiotherapy of prostate cancer. Here, we determine whether castration therapy impairs nonhomologous end-joining (NHEJ) repair of DNA double-strand breaks (DSB) by downregulating Ku70 protein expression.Experimental Design: Twenty patients with locally advanced prostate cancer were enrolled, and 6 to 12 needle core biopsy specimens were taken from the prostate of each patient before treatment. Bilateral orchidectomy was conducted in eight patients and 12 patients were treated with a GnRH agonist. After castration, two to four similar biopsies were obtained, and the levels of Ku70 and g-H2AX foci were determined by immunofluorescence in verified cancer tissues.Results: We observed that the androgen receptor binds directly to Ku70 in prostate tissue. We also found a reduction of the Ku70 protein levels in the cell nuclei in 12 of 14 patients (P < 0.001) after castration. The reduction in Ku70 expression correlated significantly with decreased serum prostate-specific antigen (PSA) levels after castration, suggesting that androgen receptor activity regulates Ku70 protein levels in prostate cancer tissue. Furthermore, a significant correlation between the reductions of Ku70 after castration versus changes induced of castration of g-H2AX foci could be seen implicating a functional linkage of decreased Ku70 levels and impaired DNA repair.Conclusions: Castration therapy results in decreased levels of the Ku70 protein in prostate cancer cells. Because the Ku70 protein is essential for the NHEJ repair of DSBs and its downregulation impairs DNA repair, this offers a possible explanation for the increased radiosensitivity of prostate cancer cells following castration.

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Section: Introductionmentioning

confidence: 97%

Castration Therapy Results in Decreased Ku70 Levels in Prostate Cancer

Al-Ubaidi

Schultz

Loseva

et al. 2013

Clinical Cancer Research

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“…Using recessed tip oxygen electrodes, which minimizes artifacts of oxygen consumption by the electrode, our group measured tumor pO 2 across microregions of tumors in a dorsal window chamber model. By comparing measured pO 2 values with theoretical simulations, local oxygen consumption was estimated as ranging from 0.83 to 2.22 cm 3 O 2 /100 g/min (59). The oxygen consumption rate of proliferating cells is three to five times higher than that of quiescent cells (230).…”

Section: Origins Of Tumor Hypoxia In Solid Tumorsmentioning

confidence: 99%

“…Kimura et al previously demonstrated that cycling hypoxia is a relatively common phenomenon in tumors using dorsal skin window chambers. They observed fluctuations in red cell flux (RCF) in tumor microvessels, which led to changes in vascular pO 2 . Variations in RCF in the poorly vascularized region led to a greater percentage of transient hypoxia as compared with the well-vascularized tumor regions (120).…”

Section: Cycling Hypoxiamentioning

confidence: 99%

“…In addition, these cells showed a higher invasive capacity relative to cells exposed to acute hypoxia (1% O 2 for 5 h) (4). Furthermore, androgen deprivation is a standard therapy for advanced prostate cancer that is used to reduce androgen receptor activation, blood flow to the prostate, and tumor hypoxia (2,5). However, androgen-dependent prostate tumors become androgen independent after longterm androgen deprivation.…”

Section: Role Of Hypoxia In Tumor Progressionmentioning

confidence: 99%

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Imaging Tumor Hypoxia to Advance Radiation Oncology

Lee

Boss

Dewhirst

2014

Antioxidants & Redox Signaling

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Significance: Most solid tumors contain regions of low oxygenation or hypoxia. Tumor hypoxia has been associated with a poor clinical outcome and plays a critical role in tumor radioresistance. Recent Advances: Two main types of hypoxia exist in the tumor microenvironment: chronic and cycling hypoxia. Chronic hypoxia results from the limited diffusion distance of oxygen, and cycling hypoxia primarily results from the variation in microvessel red blood cell flux and temporary disturbances in perfusion. Chronic hypoxia may cause either tumor progression or regressive effects depending on the tumor model. However, there is a general trend toward the development of a more aggressive phenotype after cycling hypoxia. With advanced hypoxia imaging techniques, spatiotemporal characteristics of tumor hypoxia and the changes to the tumor microenvironment can be analyzed. Critical Issues: In this review, we focus on the biological and clinical consequences of chronic and cycling hypoxia on radiation treatment. We also discuss the advanced non-invasive imaging techniques that have been developed to detect and monitor tumor hypoxia in preclinical and clinical studies. Future Directions: A better understanding of the mechanisms of tumor hypoxia with non-invasive imaging will provide a basis for improved radiation therapeutic practices. Antioxid. Redox Signal. 21, 313-337.

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“…Moreover, the use of hormone therapy -by reducing the number of cells within the tumour -improves the oxygenation of the remaining cancer cells. Recent research has shown that hormonal therapy enhances oxygenation in prostate cancer cells [53]. However, although hormonotherapy is highly efficient, some patients have progression after a period of time, which occurs because prostate cancer cells are no longer dependent on endogenous androgens.…”

Section: Hypoxia In Prostate Cancermentioning

confidence: 99%

Hypoxia in prostate cancer

Danielska

Łuniewska-Bury²,

Kuncman³

et al. 2017

Nowotwory. Journal of Oncology

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Most human solid tumours contain areas which are less oxygenated than normal tissues. Hypoxia increases resistance to radiotherapy, surgery and chemotherapy, and directly alters the function of tumour cells, stimulating them to de-differentiate and to release angiogenic factors with a view to increasing the blood and oxygen supply. Tumour hypoxia promotes malignant progression and metastasis formation. HIF-1 is a heterodimeric transcription factor composed of regulated HIF-1a and constitutively expressed HIF-1b. Tumour-associated activation of HIF-1a seems to be primarily, however the result of adaptation to oxygen shortage. The presence of the HIF-1a subunit overexpression has been confirmed in many tumours, in prostate cancer, among others; the role it plays in its progression is yet to be explained. Numerous studies strongly emphasize the importance of evaluating the status of the HIF-1a transcription factor in predicting the clinical and biochemical recurrence of prostate cancer and its resistance to castration. NOWOTWORY J Oncol 2017; 67, 2: 132-136

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Castration Therapy of Prostate Cancer Results in Downregulation of HIF-1α Levels

Cited by 23 publications

References 17 publications

Castration Therapy Results in Decreased Ku70 Levels in Prostate Cancer

Castration Therapy Results in Decreased Ku70 Levels in Prostate Cancer

Imaging Tumor Hypoxia to Advance Radiation Oncology

Hypoxia in prostate cancer

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