title: The p53-reactivating small molecule RITA induces senescence in head and neck cancer cells.
abstract: TP53 is the most commonly mutated gene in head and neck cancer (HNSCC), with mutations being associated with resistance to conventional therapy. Restoring normal p53 function has previously been investigated via the use of RITA (reactivation of p53 and induction of tumor cell apoptosis), a small molecule that induces a conformational change in p53, leading to activation of its downstream targets. In the current study we found that RITA indeed exerts significant effects in HNSCC cells. However, in this model, we found that a significant outcome of RITA treatment was accelerated senescence. RITA-induced senescence in a variety of p53 backgrounds, including p53 null cells. Also, inhibition of p53 expression did not appear to significantly inhibit RITA-induced senescence. Thus, this phenomenon appears to be partially p53-independent. Additionally, RITA-induced senescence appears to be partially mediated by activation of the DNA damage response and SIRT1 (Silent information regulator T1) inhibition, with a synergistic effect seen by combining either ionizing radiation or SIRT1 inhibition with RITA treatment. These data point toward a novel mechanism of RITA function as well as hint to its possible therapeutic benefit in HNSCC.
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America; Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Hui-Ching
authors.initials: HC
authors.lastname: Chuang
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Liang Peng
authors.initials: LP
authors.lastname: Yang
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America; Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Alison L
authors.initials: AL
authors.lastname: Fitzgerald
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Osman
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Sang Hyeok
authors.initials: SH
authors.lastname: Woo
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America; Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Myers
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Heath D
authors.initials: HD
authors.lastname: Skinner
mesh_terms: D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects* / Q000502:physiology; D005663:Furans / Q000494:pharmacology*; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D015151:Immunoblotting; D011487:Protein Conformation / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001616:beta-Galactosidase
chemical_list: D005663:Furans; C118989:NSC 652287; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D001616:beta-Galactosidase