Mutation of p53 in head and neck squamous cell carcinoma correlates with Bcl‐2 expression and increased susceptibility to cisplatin‐induced apoptosis

Andrews, Genevieve A.; Xi, Sichuan; Pomerantz, Rebecca G.; Lin, Charles; Gooding, William E.; Wentzel, Abbey L.; Li, Wu; Sidransky, David; Grandis, Jennifer R.

doi:10.1002/hed.20029

Cited by 46 publications

(36 citation statements)

References 27 publications

(3 reference statements)

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“…Although the mechanisms underlying the association of wild-type p53 with drug resistance is likely to be complex and to include effects on the cell cycle and altered apoptotic response (41), our data suggest that, in GSTP1-expressing tumors, the ability of p53 to increase GSTP1 expression will be an important part of this mechanism of drug resistance and stress response.…”

Section: Discussionmentioning

confidence: 78%

Identification and Functional Characterization of the Human Glutathione S-Transferase P1 Gene as a Novel Transcriptional Target of the p53 Tumor Suppressor Gene

Stephenson

Cao

et al. 2008

Molecular Cancer Research

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The glutathione S-transferase P1 (GSTP1) is involved in multiple cellular functions, including phase II metabolism, stress response, signaling, and apoptosis. The mechanisms underlying the significantly high GSTP1 expression in many human tumors are, however, currently not well understood. We report here that the GSTP1 gene is a heretofore unrecognized downstream transcriptional target of the tumor suppressor p53. We identified a p53-binding motif comprising two consecutive half-sites located in intron 4 of the GSTP1 gene and is highly homologous to consensus p53-binding motifs in other p53-responsive genes. Using a combination of electrophoretic mobility shift assay and DNase I footprinting analyses, we showed that wild-type p53 protein binds to the GSTP1 p53 motif and luciferase reporter assays showed the motif to be transcriptionally functional in human tumor cells. In a temperature-sensitive p53-mutant cells, levels of both p21/WAF1 and GSTP1 gene transcripts increased time dependently when cells were switched from the inactive mutant state to the wild-type p53 state. Small interfering RNA -mediated reduction of p53 expression resulted in a specific decrease in GSTP1 expression and in tumor cells with mutated p53; adenovirally mediated expression of wild-type p53 increased GSTP1 expression significantly. In a panel of early-passage brain tumor cultures from patients, high levels of GSTP1 transcripts and protein were associated with wild-type p53 and, conversely, low GSTP1 levels with mutant p53. p53 expression knockdown by small interfering RNA increased cisplatin sensitivity. The ability of wild-type p53 to transcriptionally activate the human GSTP1 gene defines a novel mechanism of protecting the genome and, potentially, of tumor drug resistance. (Mol Cancer Res 2008;6(5):843 -50)

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Section: Discussionmentioning

confidence: 78%

Identification and Functional Characterization of the Human Glutathione S-Transferase P1 Gene as a Novel Transcriptional Target of the p53 Tumor Suppressor Gene

Stephenson

Cao

et al. 2008

Molecular Cancer Research

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“…Following treatment with cisplatin, the cells were detached by trypsinization, counted, and pelleted at 1,000 rpm for 5 minutes. Cell pellets were washed once with PBS (pH 7.4) and resuspended in 100 AL Annexin V binding buffer [10 mmol/L HEPES (pH 7.4), 140 mmol/L NaCl, 2.5 mmol/L CaCl 2 ] as described previously (31). Cells (5 Â 10 5 ) were incubated with 5 AL Annexin V-Cy3 (BioVision Research Products, Mountain View, CA) at room temperature and in the absence of light for 15 minutes.…”

Section: Methodsmentioning

confidence: 99%

Mutant Epidermal Growth Factor Receptor (EGFRvIII) Contributes to Head and Neck Cancer Growth and Resistance to EGFR Targeting

Sok

Coppelli

Thomas

et al. 2006

Clinical Cancer Research

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434

364

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Purpose: Epidermal growth factor receptor (EGFR) is overexpressed in head and neck squamous cell carcinoma (HNSCC) where expression levels correlate with decreased survival. Therapies that block EGFR have shown limited efficacy in clinical trials and primarily when combined with standard therapy. The most common form of mutant EGFR (EGFRvIII) has been described in several cancers, chiefly glioblastoma.The present study was undertaken to determine the incidence of EGFRvIII expression in HNSCC and the biological consequences of EGFRvIII on tumor growth in response to EGFR targeting. Experimental Design: Thirty-three HNSCC tumors were evaluated by immunostaining and reverse transcription-PCR for EGFRvIII expression. A representative HNSCC cell line was stably transfected with an EGFRvIII expression construct. EGFRvIII-expressing cells and vectortransfected controls were compared for growth rates in vitro and in vivo as well as chemotherapyinduced apoptosis and the consequences of EGFR inhibition using the chimeric monoclonal antibody C225/cetuximab/Erbitux. Results: EGFRvIII expression was detected in 42 % of HNSCC tumors where EGFRvIII was always found in conjunction with wild-type EGFR. HNSCC cells expressing EGFRvIII showed increased proliferation in vitro and increased tumor volumes in vivo compared with vector-transfected controls. Furthermore, EGFRvIII-transfected HNSCC cells showed decreased apoptosis in response to cisplatin and decreased growth inhibition following treatment with C225 compared with vector-transfected control cells. Conclusions: EGFRvIII is expressed in HNSCC where it contributes to enhanced growth and resistance to targeting wild-type EGFR. The antitumor efficacy of EGFR targeting strategies may be enhanced by the addition of EGFRvIII-specific blockade.

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“…Extracellular and intracellular changes that promote drug metabolism, decreased cellular drug accumulation, altered expression of key molecules in the apoptotic pathway, and increased repair of DNA adducts have been reported to contribute to drug resistance (4). In HNC, alterations of key molecules mediating cisplatininduced apoptosis have been implicated in resistance (5), and mutated or overexpressed p53 and the Bcl-2 protein family, key players in regulating apoptotic pathways, were associated with HNC resistance to cisplatin-based chemotherapy (6). In addition, altered metabolism in reactive oxygen species (ROS), an essential molecule for cisplatin-induced cell killing, was also observed in HNC (7).…”

Section: Introductionmentioning

confidence: 99%

Role of Neurofilament Light Polypeptide in Head and Neck Cancer Chemoresistance

Chen

House

et al. 2012

Molecular Cancer Research

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Resistance to cisplatin-based chemotherapy is responsible for therapeutic failure of many common human cancers including cancer of head and neck (HNC). Mechanisms underlying cisplatin resistance remain unclear. In this study, we identified neurofilament light polypeptide (NEFL) as a novel hypermethylated gene associated with resistance to cisplatin-based chemotherapy in HNC. Analysis of 14 HNC cell lines revealed that downregulation of NEFL expression significantly correlated with increased resistance to cisplatin. Hypermethylation of NEFL promoter CpG islands was observed in cell lines as examined by bisulfite DNA sequencing and methylation-specific PCR (MSP) and tightly correlated with reduced NEFL mRNA and protein expression. Furthermore, in patient samples with HNC (n ¼ 51) analyzed by quantitative MSP, NEFL promoter hypermethylation was associated with resistance to cisplatin-based chemotherapy [relative risk (RR), 3.045; 95% confidence interval (CI), 1.459-6.355; P ¼ 0.007] and predicted diminished overall and disease-free survival for patients treated with cisplatin-based chemotherapy. Knockdown of NEFL by siRNA in the highly cisplatin-sensitive cell line PCI13 increased (P < 0.01) resistance to cisplatin. In cisplatin-resistant O11 and SCC25cp cells, restored expression of NEFL significantly increased sensitivity to the drug. Furthermore, NEFL physically associated with tuberous sclerosis complex 1 (TSC1), a known inhibitor of the mTOR pathway, and NEFL downregulation led to functional activation of mTOR pathway and consequentially conferred cisplatin resistance. This is the first study to show a role for NEFL in HNC chemoresistance. Our findings suggest that NEFL methylation is a novel mechanism for HNC chemoresistance and may represent a candidate biomarker predictive of chemotherapeutic response and survival in patients with HNC.

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Mutation of p53 in head and neck squamous cell carcinoma correlates with Bcl‐2 expression and increased susceptibility to cisplatin‐induced apoptosis

Abstract: These results suggest that p53 mutation directly modulates Bcl-2 expression and therefore susceptibility to chemotherapy-induced apoptosis in SCCHN cells in vitro.

Cited by 46 publications

References 27 publications

Identification and Functional Characterization of the Human Glutathione S-Transferase P1 Gene as a Novel Transcriptional Target of the p53 Tumor Suppressor Gene

Identification and Functional Characterization of the Human Glutathione S-Transferase P1 Gene as a Novel Transcriptional Target of the p53 Tumor Suppressor Gene

Mutant Epidermal Growth Factor Receptor (EGFRvIII) Contributes to Head and Neck Cancer Growth and Resistance to EGFR Targeting

Role of Neurofilament Light Polypeptide in Head and Neck Cancer Chemoresistance

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