Molecular Biologic Characteristics of Seven New Cell Lines of Squamous Cell Carcinomas of the Head and Neck and Comparison to Fresh Tumor Tissue

Welkoborsky, Hans-J.; Jacob, Roland; Riazimand, Seyed H; Bernauer, Hubert S.; Mann, Wolf J.

doi:10.1159/000071206

Cited by 35 publications

(27 citation statements)

References 27 publications

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“…Cultivation of the indicated head and neck cancer and other tumor cell lines has been described in detail [25, 61-64] (Supplementary Table SI). Cell lines constitutively expressing shRNA directed against BIM or a scrambled control were generated by transfection of pHR-THT-BIMshRNA-SFFV-eGFP or pHR-THT-scr_shRNA-SFFV-eGFP [65], respectively.…”

Section: Methodsmentioning

confidence: 99%

A combination of a ribonucleotide reductase inhibitor and histone deacetylase inhibitors downregulates EGFR and triggers BIM-dependent apoptosis in head and neck cancer

et al. 2011

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Head and neck squamous cell carcinomas (HNSCCs) are the sixth most common malignant neoplasm and more than 50% of patients succumb to this disease. HNSCCs are characterized by therapy resistance, which relies on the overexpression of anti-apoptotic proteins and on the aberrant regulation of the epidermal growth factor receptor (EGFR). As inherent and acquired resistance to therapy counteracts improvement of long-term survival, novel multi-targeting strategies triggering cancer cell death are urgently required. We investigated how induction of replicational stress by the ribonucleotide reductase inhibitor hydroxyurea (HU) combined with histone deacetylase inhibitors (HDACi) exerts anti-tumor activity. We treated HNSCC cell lines and freshly isolated tumor cells with HDACi, such as the clinically approved anti-epileptic drug valproic acid (VPA), in combination with HU. Our data demonstrate that at clinically achievable levels VPA/HU combinations efficiently block proliferation as well as clonogenic survival, and trigger apoptosis of HNSCC cells. In the presence of VPA/HU, such tumor cells increase expression of the pro-apoptotic BCL-2 family protein BIM, independent of wild-type p53 signaling and in the absence of increased expression of the p53 targets PUMA and BAX. The pro-apoptotic activity of BIM in HNSCCs was found critical for tumor cell death; ectopic overexpression of BIM induced HNSCC apoptosis and RNAi-mediated depletion of BIM protected HNSCC cells from VPA/HU. Also, significantly elevated BIM levels (p<0.01) were detectable in the apoptotic tumor centers versus proliferating tumor margins in HNSCC patients (n=31), underlining BIM's clinical relevance. Importantly, VPA/HU treatment additionally reduces expression and cell surface localization of EGFR. Accordingly, in a xenograft mouse model, VPA/HU efficiently blocked tumor growth (P<0.001) correlating with BIM induction and EGFR downregulation. We provide a molecular rationale for the potent anti-cancer activities of this drug combination. Our data suggest its exploitation as a potential strategy for the treatment of HNSCC and other tumor entities characterized by therapy resistance linked to dysregulated EGFR activation.

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Section: Methodsmentioning

confidence: 99%

A combination of a ribonucleotide reductase inhibitor and histone deacetylase inhibitors downregulates EGFR and triggers BIM-dependent apoptosis in head and neck cancer

et al. 2011

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“…HNSCC cell line Hun was previously established and characterized in our laboratory. 13,14 Cells had been characterized by comparative genomic hybridization (CGH) 3 months prior to the experiments.…”

Section: Methodsmentioning

confidence: 99%

Activation of mitogen‐activated protein kinase extracellular signal‐related kinase in head and neck squamous cell carcinomas after irradiation as part of a rescue mechanism

et al. 2010

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“…For our experiments we used the head and neck squamous cell carcinoma cell line HNCCUM-01T (16). This cell line has been used in previous hypermethylation experiments (12).…”

Section: Pharmacological Genome Demethylation Increases Radiosensitivmentioning

confidence: 99%

Pharmacological genome demethylation increases radiosensitivity of head and neck squamous carcinoma cells

Brieger

Mann²,

Pongsapich³

et al. 2011

Int J Mol Med

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Abstract. Aberrant inactivation of tumor suppressor genes by promoter hypermethylation has been recognized as a crucial step of tumor development and is related to aggressiveness and therapy resistance. To identify potential novel treatment strategies, we evaluated pharmacological genome demethylation for the increase of irradiation treatment effectiveness in head and neck squamous cell carcinoma (HNSCC) in this in vitro study. HNSCC cells were cultured with 2 different concentrations of 5-azacytidine (5-Aza) for 72 h, followed by a single fraction irradiation with 4 or 50 Gy, respectively. To show successful genome demethylation, the methylation status of the tumor suppressor gene hic1 (hypermethylated in cancer) promoter was analyzed by methylation specific PCR (MSP) as well as hic1 transcription by quantitative RT-PCR. Survival, apoptosis, viability, and migration of the tumor cells were analyzed as functional parameters of combined treatment response. After 5-Aza treatment the hic1 promoter was demethylated and gene transcription restored demonstrating genome demethylation. 5-Aza treated cells tended to be less viable and showed decreased survival indicated by lower colony numbers. Apoptosis and migration were not affected. The combined application of irradiation and 5-Aza significantly reduced survival compared to the single treatments. Accordingly, apoptosis was strongly increased after combined 4 Gy/5-Aza treatment. Viability was not additionally affected by combined treatment. Migration was affected weakly by combined high dosage irradiation/5-Aza treatment. Our data show that the combined application of 5-Aza and irradiation is effective in vitro. A demethylating concept prior to irradiation should be further evaluated for its potential to reduce irradiation resistance.

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Molecular Biologic Characteristics of Seven New Cell Lines of Squamous Cell Carcinomas of the Head and Neck and Comparison to Fresh Tumor Tissue

Cited by 35 publications

References 27 publications

A combination of a ribonucleotide reductase inhibitor and histone deacetylase inhibitors downregulates EGFR and triggers BIM-dependent apoptosis in head and neck cancer

A combination of a ribonucleotide reductase inhibitor and histone deacetylase inhibitors downregulates EGFR and triggers BIM-dependent apoptosis in head and neck cancer

Activation of mitogen‐activated protein kinase extracellular signal‐related kinase in head and neck squamous cell carcinomas after irradiation as part of a rescue mechanism

Pharmacological genome demethylation increases radiosensitivity of head and neck squamous carcinoma cells

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