title: Reactive oxygen species and p21Waf1/Cip1 are both essential for p53-mediated senescence of head and neck cancer cells.
abstract: Treatment of head and neck squamous cell carcinoma, HNSCC, often requires multimodal therapy, including radiation therapy. The efficacy of radiotherapy in controlling locoregional recurrence, the most frequent cause of death from HNSCC, is critically important for patient survival. One potential biomarker to determine radioresistance is TP53 whose alterations are predictive of poor radiation response. DNA-damaging reactive oxygen species (ROS) are a by-product of ionizing radiation that lead to the activation of p53, transcription of p21(cip1/waf1) and, in the case of wild-type TP53 HNSCC cells, cause senescence. The expression of p21 and production of ROS have been associated with the induction of cellular senescence, but the intricate relationship between p21 and ROS and how they work together to induce senescence remains elusive. For the first time, we show that persistent exposure to low levels of the ROS, hydrogen peroxide, leads to the long-term expression of p21 in HNSCC cells with a partially functional TP53, resulting in senescence. We conclude that the level of ROS is crucial in initiating p53's transcription of p21 leading to senescence. It is p21's ability to sustain elevated levels of ROS, in turn, that allows for a long-term oxidative stress, and ensures an active p53-p21-ROS signaling loop. Our data offer a rationale to consider the use of either ROS inducing agents or therapies that increase p21 expression in combination with radiation as approaches in cancer therapy and emphasizes the importance of considering TP53 status when selecting a patient's treatment options.
authors.affiliation: 1] Graduate School of Biomedical Sciences, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA [2] Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: Fitzgerald
authors.affiliation: Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Osman
authors.affiliation: Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: T-X
authors.initials: TX
authors.lastname: Xie
authors.affiliation: Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: A
authors.initials: A
authors.lastname: Patel
authors.affiliation: Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX.
authors.forename: H
authors.initials: H
authors.lastname: Skinner
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, TX.
authors.forename: V
authors.initials: V
authors.lastname: Sandulache
authors.affiliation: Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: J N
authors.initials: JN
authors.lastname: Myers
mesh_terms: D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000502:physiology / Q000528:radiation effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D006258:Head and Neck Neoplasms / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D015151:Immunoblotting; D018384:Oxidative Stress / Q000502:physiology; D010766:Phosphorylation; D011839:Radiation, Ionizing; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D006861:Hydrogen Peroxide