Oropharyngeal Carcinomas Harboring HPV-E6 Display Resistance to Liberation of P53 and Sensitivity to Oxidative Stress

Abstract

Objectives:

Analyze the effect of (1) Nutlin-3, a small molecule liberator of p53, on human papillomavirus (HPV) E6 protein-driven oropharyngeal squamous cell carcinoma (OPSCC) cell lines and (2) the response of such cell lines to oxidative stress.

Methods:

Reproducible drug sensitivity (MTT) and clonogenic assays were performed, with treatments with Nutlin-3 and hydrogen peroxide. Western blots were performed for p53 and MDM2 expression.

Results:

Our data show that UM-SCC-47, an oropharyngeal cancer cell line harboring HPV E6, displays no growth or radiation sensitivity to Nutlin-3. As expected from previous work UM-SCC-74A, an oropharyngeal cancer cell line not driven by HPV and harboring wild-type p53, displayed both growth and radiation sensitivity. Similarly, UM-SCC-4, an oropharyngeal cancer cell line not driven by HPV but harboring mutant p53, displayed minimal growth or radiation sensitivity. Early results show that UM-SCC-47 displays significantly greater sensitivity to oxidative stress than cell lines negative for HPV and harboring wild-type p53.

Conclusions:

We have shown for the first time that Nutlin-3 has no effect in cells expressing HPV E6. We have also shown that p53-deficient cells have an impaired response to oxidative stress. Such impaired regulation of oxidative stress and metabolism could be exploited in a number of different ways and may have implications for the targeting of cancers that have mutant or no p53, which typically carry a worse prognosis.