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Replication Stress Leading to Apoptosis Within the S-Phase

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Published OnlineFirst August 8, 2017; DOI: 10.1158/1078-0432.CCR-17-0947 Cancer Therapy: Preclinical Clinical Cancer Research Replication Stress Leading to Apoptosis within the S-phase Contributes to Synergism between Vorinostat and AZD1775 in HNSCC Harboring High-Risk TP53 Mutation Noriaki Tanaka1, Ameeta A. Patel1, Lin Tang1, Natalie L. Silver2, Antje Lindemann1, Hideaki Takahashi1, Roman Jaksik3, Xiayu Rao4, Nene N. Kalu5, Tseng-Cheng Chen6, Jiping Wang1, Mitchell J. Frederick7, Faye Johnson5, Frederico O. Gleber-Netto1, Siqing Fu8, Marek Kimmel3, Jing Wang4, Walter N. Hittelman9, Curtis R. Pickering1, Jeffrey N. Myers1, and Abdullah A. Osman1 Abstract Purpose: The cure rate for patients with advanced head and neck Results: We found that vorinostat synergizes with AZD1775 squamous cell carcinoma (HNSCC) remains poor due to resis- in vitro to inhibit growth of HNSCC cells harboring high-risk tance to standard therapy primarily consisting of chemoradiation. mutp53. These drugs interact synergistically to induce DNA As mutation of TP53 in HNSCC occurs in 60% to 80% of non– damage, replication stress associated with impaired Rad51- HPV-associated cases and is in turn associated with resistance to mediated HR through activation of CDK1, and inhibition of these treatments, more effective therapies are needed. In this study, Chk1 phosphorylation, culminating in an early apoptotic cell we evaluated the efficacy of a regimen combining vorinostat and death during the S-phase of the cell cycle. The combination of AZD1775 in HNSCC cells with a variety of p53 mutations. vorinostat and AZD1775 inhibits tumor growth and angiogen- Experimental Design: Clonogenic survival assays and an esis in vivo in an orthotopic mouse model of oral cancer and orthotopic mouse model of oral cancer were used to examine prolongs animal survival. the in vitro and in vivo sensitivity of high-risk mutant p53 HNSCC Conclusions: Vorinostat synergizes with AZD1775 in cell lines to vorinostat in combination with AZD1775. Cell cycle, HNSCC cells with mutant p53 in vitro and in vivo.Astrategy replication stress, homologous recombination (HR), live cell combining HDAC and WEE1 inhibition deserves further imaging, RNA sequencing, and apoptosis analyses were per- clinical investigation in patients with advanced HNSCC. Clin formed to dissect molecular mechanisms. Cancer Res; 23(21); 6541–54. Ó2017 AACR. Introduction 1Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas. 2Department of Otolaryngology, Division of Head and neck squamous cell carcinoma (HNSCC) is the Head and Neck Oncologic Surgery, University of Florida College of Medicine, seventh most common cancer worldwide (1). The cure rate for 3 Gainesville, Florida. Department of Statistics, Rice University, Houston, Texas. patients with advanced HNSCC remains poor due to resistance 4Department of Bioinformatics and Computational Biology, The University of 5 to standard therapy primarily consisting of cisplatin and radi- Texas MD Anderson Cancer Center, Houston, Texas. Department of Thoracic/ TP53 Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer ation. Mutation of in HNSCC occurs in 60% to 80% of Center, Houston, Texas. 6Department of Otolaryngology, National Taiwan human papillomavirus (HPV)-negative cases (2, 3) and is University Hospital, Taipei, Taiwan. 7Department of Otolaryngology/Head and associated with resistance to these treatments. Recently, we Neck Surgery, Baylor College of Medicine, Houston, Texas. 8Department of developed a novel computational approach termed evolution- Investigational Cancer Therapeutics, The University of Texas MD Anderson ary action (EAp53), which can stratify patients with tumors 9 Cancer Center, Houston, Texas. Department of Experimental Therapeutics, harboring TP53 mutationsashighorlowrisk.Patientswith The University of Texas MD Anderson Cancer, Houston, Texas. high-risk TP53 mutations had the poorest survival outcomes, Note: Supplementary data for this article are available at Clinical Cancer shortest time to the development of distant metastases, and Research Online (http://clincancerres.aacrjournals.org/). increased resistance to cisplatin-based therapy (4, 5). As the N. Tanaka, A.A. Patel, J.N. Myers, and A.A. Osman contributed equally to this group of tumors with this high-risk mutation shows resistance article. to cisplatin or radiation, we are interested in the development Corresponding Authors: JeffreyN.MyersandAbdullahA.Osman,The of novel therapeutic approaches to overcome this resistance University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, and improve treatment outcomes. WEE1 is a kinase that has Houston, TX 77030. Phone: 713-745-2667; Fax: 713-794-4662; E-mail: been linked to DNA damage–induced S-phase replication stress [email protected]; and [email protected] and G2–M arrest, owing to its ability to inactivate cyclin- doi: 10.1158/1078-0432.CCR-17-0947 dependent kinase 1 (CDK1) through phosphorylation of the Ó2017 American Association for Cancer Research. Tyr15 residue (6–10). Recently, we demonstrated that the www.aacrjournals.org 6541 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst August 8, 2017; DOI: 10.1158/1078-0432.CCR-17-0947 Tanaka et al. alone or in combination with AZD1775 results in increased Translational Relevance markers of replication stress, DNA damage response, and Although the treatment of locally advanced head and neck impaired Rad51-mediated homologous recombination (HR), cancer has evolved recently, the cure rate for patients with leading to an early apoptotic cell death during the S-phase and aggressive tumors and high risk of failure remains poor due to subsequently in the G2–M cell-cycle phase. Using live cell imag- resistance to standard chemoradiotherapy. As TP53, the gene ing, RNA sequencing (RNA-seq) analyses and reverse-phase pro- that encodes the p53 protein, is by far the most commonly tein array (RPPA) proteomic profiling, we further provide evi- mutated gene found in head and neck cancer and is, in turn, dence that the mechanism of the synergistic interaction between associated with treatment failure and poor survival outcomes, these two drugs may be in part due to vorinostat's ability to more effective therapies are urgently needed. In this study, we epigenetically modulate expression of a transcript-signature con- evaluate the efficacy of combining the HDAC inhibitor, vor- taining genes involved in regulating replication stress, mitosis, inostat, and the WEE1 inhibitor, AZD1775, in head and neck and the cell-cycle checkpoints in p53-mutant HNSCC cells. Taken tumor cells expressing high-risk mutant p53. Our data dem- together, our findings support a strategy, including a combination onstrate the vulnerability of HNSCC to vorinostat and of WEE1 and HDAC inhibition, which is a novel therapeutic AZD1775 through induction of replication stress associated regimen warranting investigation in patients with advanced with decreased Rad51-mediated homologous recombination. HNSCC. Thus, we provide preclinical foundation for initiation of clinical trials using combination of HDACs and WEE1 inhi- bitors, particularly for patients with advanced and recurrent Materials and Methods metastatic HNSCC tumors. Tissue culture, reagents, and generation of stable cell lines The HNSCC cell line PCI13 lacking endogenous expression of p53 was obtained from the laboratory of Dr. Jennifer Grandis (University of Pittsburgh, Pittsburgh, PA) in August 2008 and engineered to stably express constructs containing wild-type p53 WEE1 kinase inhibitor AZD1775 sensitizes HNSCC cells har- (wtp53), high-risk EA score mutant p53 (C238F and G245D), as boring high-risk TP53 mutations to cisplatin both in vitro and described previously (4). The HNSCC cell lines, HN30-expressing in vivo through induction of persistent DNA damage response wtp53 and HN31-expressing mutp53, were obtained in Decem- associated with mitotic delay and subsequent senescence (11). ber 2008 from the laboratory of Dr. John Ensley (Wayne State Modulation of the acetylation status of histones and transcrip- University, Detroit, MI). OSC-19 was obtained from Health tion factors is an essential mechanism for regulating gene expres- Science Research Resource Bank (HSRRB) in 2010. Detroit562 sion (12, 13). Histone acetylation is generally associated with was purchased from ATCC in 2009. HN5 was obtained from elevated transcription, whereas deacetylated histones are often Dr. D.M. Easty (Ludwig Institute for Cancer Research, London, linked to repressed transcription (14). Histone deacetylases United Kingdom) in 2003. The cell lines were maintained in (HDAC) act enzymatically to remove the acetyl group from DMEM, supplemented with 10% FBS, L-glutamine, sodium pyru- histones and silence gene expression (14). Elevated activities of vate, nonessential amino acids, and vitamin solution, and incu- HDACs have been observed in several human malignancies, bated at 37 Cin5%CO2 and 95% air. The identity of all cell lines including HNSCC, and their overexpression is associated with was authenticated using short tandem repeat testing within poorer prognosis in oral cancer patients (2, 15, 16). Collectively, 6 months of cell use. The WEE1 inhibitor AZD1775 was provided these findings indicate that histone deacetylation may represent a by AstraZeneca through a collaborative agreement arranged by potential therapeutic target
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    de Camargo et al. BMC Genomics (2015) 16:384 DOI 10.1186/s12864-015-1595-0 RESEARCH ARTICLE Open Access Non-synonymous mutations mapped to chromosome X associated with andrological and growth traits in beef cattle Gregório Miguel Ferreira de Camargo1,2,3, Laercio R Porto-Neto2, Matthew J Kelly3, Rowan J Bunch2, Sean M McWilliam2, Humberto Tonhati1, Sigrid A Lehnert2, Marina R S Fortes3* and Stephen S Moore4 Abstract Background: Previous genome-wide association analyses identified QTL regions in the X chromosome for percentage of normal sperm and scrotal circumference in Brahman and Tropical Composite cattle. These traits are important to be studied because they are indicators of male fertility and are correlated with female sexual precocity and reproductive longevity. The aim was to investigate candidate genes in these regions and to identify putative causative mutations that influence these traits. In addition, we tested the identified mutations for female fertility and growth traits. Results: Using a combination of bioinformatics and molecular assay technology, twelve non-synonymous SNPs in eleven genes were genotyped in a cattle population. Three and nine SNPs explained more than 1% of the additive genetic variance for percentage of normal sperm and scrotal circumference, respectively. The SNPs that had a major influence in percentage of normal sperm were mapped to LOC100138021 and TAF7L genes; and in TEX11 and AR genes for scrotal circumference. One SNP in TEX11 was explained ~13% of the additive genetic variance for scrotal circumference at 12 months. The tested SNP were also associated with weight measurements, but not with female fertility traits.
  • Emi1 (FBXO5) (Center) Rabbit Polyclonal Antibody Product Data

    Emi1 (FBXO5) (Center) Rabbit Polyclonal Antibody Product Data

    OriGene Technologies, Inc. 9620 Medical Center Drive, Ste 200 Rockville, MD 20850, US Phone: +1-888-267-4436 [email protected] EU: [email protected] CN: [email protected] Product datasheet for AP51634PU-N Emi1 (FBXO5) (Center) Rabbit Polyclonal Antibody Product data: Product Type: Primary Antibodies Applications: WB Recommended Dilution: ELISA: 1/1000. Western Blot: 1/100-1/500. Reactivity: Human Host: Rabbit Isotype: Ig Clonality: Polyclonal Immunogen: KLH conjugated synthetic peptide between 191-221 amino acids from the Central region of Human FBXO5. Specificity: This antibody recognizes Human FBXO5 (Center). Formulation: PBS containing 0.09% (W/V) Sodium Azide as preservative State: Aff - Purified State: Liquid purified Ig fraction Concentration: lot specific Purification: Affinity Chromatography on Protein A Conjugation: Unconjugated Storage: Store undiluted at 2-8°C for one month or (in aliquots) at -20°C for longer. Avoid repeated freezing and thawing. Stability: Shelf life: one year from despatch. Gene Name: Homo sapiens F-box protein 5 (FBXO5), transcript variant 2 Database Link: Entrez Gene 26271 Human Q9UKT4 This product is to be used for laboratory only. Not for diagnostic or therapeutic use. View online » ©2021 OriGene Technologies, Inc., 9620 Medical Center Drive, Ste 200, Rockville, MD 20850, US 1 / 2 Emi1 (FBXO5) (Center) Rabbit Polyclonal Antibody – AP51634PU-N Background: This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of the ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination.
  • Human Lectins, Their Carbohydrate Affinities and Where to Find Them

    Human Lectins, Their Carbohydrate Affinities and Where to Find Them

    biomolecules Review Human Lectins, Their Carbohydrate Affinities and Where to Review HumanFind Them Lectins, Their Carbohydrate Affinities and Where to FindCláudia ThemD. Raposo 1,*, André B. Canelas 2 and M. Teresa Barros 1 1, 2 1 Cláudia D. Raposo * , Andr1 é LAQVB. Canelas‐Requimte,and Department M. Teresa of Chemistry, Barros NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2829‐516 Caparica, Portugal; [email protected] 12 GlanbiaLAQV-Requimte,‐AgriChemWhey, Department Lisheen of Chemistry, Mine, Killoran, NOVA Moyne, School E41 of ScienceR622 Co. and Tipperary, Technology, Ireland; canelas‐ [email protected] NOVA de Lisboa, 2829-516 Caparica, Portugal; [email protected] 2* Correspondence:Glanbia-AgriChemWhey, [email protected]; Lisheen Mine, Tel.: Killoran, +351‐212948550 Moyne, E41 R622 Tipperary, Ireland; [email protected] * Correspondence: [email protected]; Tel.: +351-212948550 Abstract: Lectins are a class of proteins responsible for several biological roles such as cell‐cell in‐ Abstract:teractions,Lectins signaling are pathways, a class of and proteins several responsible innate immune for several responses biological against roles pathogens. such as Since cell-cell lec‐ interactions,tins are able signalingto bind to pathways, carbohydrates, and several they can innate be a immuneviable target responses for targeted against drug pathogens. delivery Since sys‐ lectinstems. In are fact, able several to bind lectins to carbohydrates, were approved they by canFood be and a viable Drug targetAdministration for targeted for drugthat purpose. delivery systems.Information In fact, about several specific lectins carbohydrate were approved recognition by Food by andlectin Drug receptors Administration was gathered for that herein, purpose. plus Informationthe specific organs about specific where those carbohydrate lectins can recognition be found by within lectin the receptors human was body.