Die Strahlensensitivität humaner Tumorzelllinien ist unabhängig von der basalen HIF-1α-Expression

Schilling, Daniela; Bayer, Christine; Emmerich, Karl-Heinz; Molls, M.; Vaupel, Peter; Huber, Roman; Multhoff, Gabriele

doi:10.1007/s00066-011-0051-6

Cited by 12 publications

(5 citation statements)

References 30 publications

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“…1A, black bars, right graph). As demonstrated previously, the inability of H1339 cells to up-regulate HIF-1α in response to hypoxia can neither be explained by varying cell densities, absence / presence of growth factors nor by reoxygenation effects [13]. In contrast to HIF-1α, HIF-2α was up-regulated upon hypoxic exposure in both tumor cell lines (Fig.…”

Section: Resultssupporting

confidence: 65%

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Radiosensitization of Normoxic and Hypoxic H1339 Lung Tumor Cells by Heat Shock Protein 90 Inhibition Is Independent of Hypoxia Inducible Factor-1α

Schilling

Bayer

et al. 2012

PLoS ONE

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BackgroundIonizing irradiation is a commonly accepted treatment modality for lung cancer patients. However, the clinical outcome is hampered by normal tissue toxicity and tumor hypoxia. Since tumors often have higher levels of active heat shock protein 90 (Hsp90) than normal tissues, targeting of Hsp90 might provide a promising strategy to sensitize tumors towards irradiation. Hsp90 client proteins include oncogenic signaling proteins, cell cycle activators, growth factor receptors and hypoxia inducible factor-1α (HIF-1α). Overexpression of HIF-1α is assumed to promote malignant transformation and tumor progression and thus might reduce the accessibility to radiotherapy.Methodology/Principal FindingsHerein, we describe the effects of the novel Hsp90 inhibitor NVP-AUY922 and 17-allylamino-17-demethoxygeldanamycin (17-AAG), as a control, on HIF-1α levels and radiosensitivity of lung carcinoma cells under normoxic and hypoxic conditions. NVP-AUY922 exhibited a similar biological activity to that of 17-AAG, but at only 1/10 of the dose. As expected, both inhibitors reduced basal and hypoxia-induced HIF-1α levels in EPLC-272H lung carcinoma cells. However, despite a down-regulation of HIF-1α upon Hsp90 inhibition, sensitivity towards irradiation remained unaltered in EPLC-272H cells under normoxic and hypoxic conditions. In contrast, treatment of H1339 lung carcinoma cells with NVP-AUY922 and 17-AAG resulted in a significant up-regulation of their initially high HIF-1α levels and a concomitant increase in radiosensitivity.Conclusions/SignificanceIn summary, our data show a HIF-1α-independent radiosensitization of normoxic and hypoxic H1339 lung cancer cells by Hsp90 inhibition.

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Section: Resultssupporting

confidence: 65%

“…Although elevated HIF-1α levels were previously reported to be predictive for radioresistance [11] our findings show an increased radiosensitivity in tumors with high basal HIF-1α levels. This finding was confirmed in a larger panel of tumor cell lines derived from different entities [24] .…”

Section: Resultssupporting

confidence: 60%

Radiosensitization of Normoxic and Hypoxic H1339 Lung Tumor Cells by Heat Shock Protein 90 Inhibition Is Independent of Hypoxia Inducible Factor-1α

Schilling

Bayer

et al. 2012

PLoS ONE

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“…In our animal study, immunohistochemical analysis clearly revealed p21 expression and apoptosis in tumor tissues within 4 days after RT rather than 14 days later, when the molecular responses may have passed, potentially indicating that the change in tumor size was a net effect of RT. Clinical trials and mechanistic studies are urgently required to identify appropriate radiosensitizers for administering RT for oral squamous cell carcinoma [48–51]. Concurrent chemoradiation therapy has improved locoregional control and patient survival; however, locoregional failure remains a significant problem [52, 53].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-17-5p regulated apoptosis-related protein expression and radiosensitivity in oral squamous cell carcinoma caused by betel nut chewing

Liu

2016

Oncotarget

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Betel nut chewing is associated with oral cavity cancer. Radiotherapy is one of the therapeutic approaches. Here, we used miR-17-5p antisense oligonucleotides (AS-ODNs) and human apoptosis protein array to clarify which apoptosis-related proteins are increased or decreased by miR-17-5p in betel nut chewing- oral squamous cell carcinoma OC3 cells. Furthermore, miR-17-5p AS-ODN was used to evaluate the radio-sensitization effects both in vitro and in vivo. An OC3 xenograft tumor model in severe combined immunodeficiency mice was used to determine the effect of miR-17-5p AS ODN on tumor irradiation. We simultaneously detected the relative expressions of 35 apoptosis-related proteins in irradiated OC3 cells that were treated with miR-17-5p AS-ODN or a control ODN. Several proteins, including p21, p53, TNF RI, FADD, cIAP-1, HIF-1α, and TRAIL R1, were found to be up- or downregulated by miR-17-5p in OC3 cells; their expression patterns were also confirmed by Western blotting. We further clarified the role of p53 in irradiated OC3 cells, using a p53 overexpression strategy. The results revealed that the enhancement of p53 expression significantly enhanced radiation-induced G2/M arrest of the OC3 cells. In the in vivo study, treatment of miR-17-5p AS-ODN before irradiation significantly enhanced p53 expression and reduced tumor growth. These results suggest that miR-17-5p increases or decreases apoptosis-related proteins in irradiated OC3 cells; its effect on p53 protein expression contributes to the modulation of the radiosensitivity of the OC3 cells.

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“…It was proved that HIF-1 plays a pivotal role in hypoxia-induced tumor radioresistance (Moeller and Dewhirst, 2006; Harada, 2011). In this context, our own investigations revealed no correlation between basal HIF-1α levels and the survival fraction in irradiated tumor cell lines implying that basal HIF-1α levels in human tumor cell lines obviously do not predict their radiosensitivity under normoxia (Schilling et al, 2012a). Moreover, HIF-1α has been found as being responsible for genetic instability to down-regulated MMR proteins by inhibiting the MMR proteins MSH-2 and MSH-6, thereby decreasing levels of the MSH-2/MSH-6 complex, MutSα, which recognizes base mismatches.…”

Section: Genetic Instabilitymentioning

confidence: 95%

Radiation, Inflammation, and Immune Responses in Cancer

Multhoff¹,

Radons²

2012

Front. Oncol.

162

128

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Chronic inflammation has emerged as one of the hallmarks of cancer. Inflammation also plays a pivotal role in modulating radiation responsiveness of tumors. As discussed in this review, ionizing radiation (IR) leads to activation of several transcription factors modulating the expression of numerous mediators in tumor cells and cells of the microenvironment promoting cancer development. Novel therapeutic approaches thus aim to interfere with the activity or expression of these factors, either in single-agent or combinatorial treatment or as supplements of the existing therapeutic concepts. Among them, NF-κB, STAT-3, and HIF-1 play a crucial role in radiation-induced inflammatory responses embedded in a complex inflammatory network. A great variety of classical or novel drugs including nutraceuticals such as plant phytochemicals have the capacity to interfere with the inflammatory network in cancer and are considered as putative radiosensitizers. Thus, targeting the inflammatory signaling pathways induced by IR offers the opportunity to improve the clinical outcome of radiation therapy by enhancing radiosensitivity and decreasing putative metabolic effects. Since inflammation and sex steroids also impact tumorigenesis, a therapeutic approach targeting glucocorticoid receptors and radiation-induced production of tumorigenic factors might be effective in sensitizing certain tumors to IR.

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Die Strahlensensitivität humaner Tumorzelllinien ist unabhängig von der basalen HIF-1α-Expression

Abstract: Our data suggest that basal HIF-1α levels in human tumor cell lines do not predict their radiosensitivity under normoxia.

Cited by 12 publications

References 30 publications

Radiosensitization of Normoxic and Hypoxic H1339 Lung Tumor Cells by Heat Shock Protein 90 Inhibition Is Independent of Hypoxia Inducible Factor-1α

Radiosensitization of Normoxic and Hypoxic H1339 Lung Tumor Cells by Heat Shock Protein 90 Inhibition Is Independent of Hypoxia Inducible Factor-1α

MicroRNA-17-5p regulated apoptosis-related protein expression and radiosensitivity in oral squamous cell carcinoma caused by betel nut chewing

Radiation, Inflammation, and Immune Responses in Cancer

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