Genetic Disruption of KEAP1/CUL3 E3 Ubiquitin Ligase Complex Components is a Key Mechanism of NF-KappaB Pathway Activation in Lung Cancer Kelsie L. Thu,

Slides:

Advertisements

Similar presentations

YEATS4 Is a Novel Oncogene Amplified in Non– Small Cell Lung Cancer That Regulates the p53 Pathway Speaker:Dai-Wei Hsuan Adviser:Dr. Guor-Mour, Her Data:2015/04/22.

Advertisements

Manish R. Patel, DO, Blake A

Nicotinamide Phosphoribosyltransferase: A Potent Therapeutic Target in Non-small Cell Lung Cancer with Epidermal Growth Factor Receptor-Gene Mutation

Aldehyde Dehydrogenase 1A1 Possesses Stem-Like Properties and Predicts Lung Cancer Patient Outcome Xiao Li, MD, Liyan Wan, MD, Jian Geng, MD, Chin-Lee.

Carcinoma NOS is a Common Histologic Diagnosis and is Increasing in Proportion Among Non-small Cell Lung Cancer Histologies Sai-Hong Ignatius Ou, MD,

EZH2 Promotes E2F-Driven SCLC Tumorigenesis through Modulation of Apoptosis and Cell-Cycle Regulation Roland Hubaux, PhD, Kelsie L. Thu, BSc, Bradley.

Group IIa secretory phospholipase expression correlates with group IIa secretory phospholipase inhibition–mediated cell death in K-ras mutant lung cancer.

Volume 67, Issue 2, Pages (August 2017)

WT1 Promotes Invasion of NSCLC via Suppression of CDH1

Inactivation of Both FHIT and p53 Cooperate in Deregulating Proliferation-Related Pathways in Lung Cancer Francesca Andriani, PharmD, Elena Roz, MD,

Manish R. Patel, DO, Blake A

CDKN2A/p16 Inactivation Mechanisms and Their Relationship to Smoke Exposure and Molecular Features in Non–Small-Cell Lung Cancer Kit W. Tam, MD, MHS,

DNMT3B Overexpression by Deregulation of FOXO3a-Mediated Transcription Repression and MDM2 Overexpression in Lung Cancer Yi-Chieh Yang, MS, Yen-An Tang,

Deregulation of SLIT2-Mediated Cdc42 Activity Is Associated with Esophageal Cancer Metastasis and Poor Prognosis Ruo-Chia Tseng, PhD, Jia-Ming Chang,

Nicotine Induces Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor by α1 Nicotinic Acetylcholine Receptor–Mediated Activation in.

AZGP1 Autoantibody Predicts Survival and Histone Deacetylase Inhibitors Increase Expression in Lung Adenocarcinoma Daniel L. Albertus, BS, Christopher.

ITPKA Gene Body Methylation Regulates Gene Expression and Serves as an Early Diagnostic Marker in Lung and Other Cancers Yi-Wei Wang, PhD, Xiaotu Ma,

A Novel IMP1 Inhibitor, BTYNB, Targets c-Myc and Inhibits Melanoma and Ovarian Cancer Cell Proliferation Lily Mahapatra, Neal Andruska, Chengjian Mao,

Molecular Predictors of Sensitivity to the MET Inhibitor PHA in Lung Carcinoma Cells Daisuke Matsubara, MD, PhD, Shumpei Ishikawa, MD, PhD, Sachiko.

MicroRNA-489 Plays an Anti-Metastatic Role in Human Hepatocellular Carcinoma by Targeting Matrix Metalloproteinase-7 Yixiong Lin, Jianjun Liu, Yuqi Huang,

Characterization of microRNA transcriptome in tumor, adjacent, and normal tissues of lung squamous cell carcinoma Jun Wang, MD, PhD, Zhi Li, MD, PhD,

Chandra M.V. Goparaju, PhD Journal of Thoracic Oncology

TGM2: A Cell Surface Marker in Esophageal Adenocarcinomas

Interleukin-17 and Prostaglandin E2 Are Involved in Formation of an M2 Macrophage- Dominant Microenvironment in Lung Cancer Lunxu Liu, MD, PhD, Dongxia.

Prognostic Significance of TAZ Expression in Resected Non-Small Cell Lung Cancer Mian Xie, MD, PhD, Li Zhang, MD, Chao-Sheng He, MD, Jin-Hui Hou, MD,

Timon P. H. Buys, BSc, Sarit Aviel-Ronen, MD, Thomas K

Identification and Validation of Long Noncoding RNA Biomarkers in Human Non–Small- Cell Lung Carcinomas Hui Yu, MD, Qinghua Xu, PhD, Fang Liu, PhD, Xun.

Characterization of Fibroblast Growth Factor Receptor 1 in Small-Cell Lung Cancer Anish Thomas, MD, Jih-Hsiang Lee, MD, Zied Abdullaev, PhD, Kang-Seo.

Expression of CDCA3 Is a Prognostic Biomarker and Potential Therapeutic Target in Non–Small Cell Lung Cancer Mark N. Adams, PhD, Joshua T. Burgess, PhD,

Aldehyde Dehydrogenase 1A1 Possesses Stem-Like Properties and Predicts Lung Cancer Patient Outcome Xiao Li, MD, Liyan Wan, MD, Jian Geng, MD, Chin-Lee.

Molecular Therapy - Nucleic Acids

Association of Epidermal Growth Factor Receptor Activating Mutations with Low ERCC1 Gene Expression in Non-small Cell Lung Cancer David R. Gandara, MD,

Preclinical Rationale for Use of the Clinically Available Multitargeted Tyrosine Kinase Inhibitor Crizotinib in ROS1-Translocated Lung Cancer Hiroyuki.

Whole-Genome Sequencing Analysis Identifies a Distinctive Mutational Spectrum in an Arsenic-Related Lung Tumor Victor D. Martinez, PhD, Kelsie L. Thu,

Chandra Goparaju, PhD, Jessica S

Frequent Coamplification and Cooperation between C-MYC and PVT1 Oncogenes Promote Malignant Pleural Mesothelioma Erick Riquelme, PhD, Milind B. Suraokar,

Co-Overexpression of Cyclooxygenase-2 and Microsomal Prostaglandin E Synthase-1 Adversely Affects the Postoperative Survival in Non-small Cell Lung Cancer

Nicotine Induces Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor by α1 Nicotinic Acetylcholine Receptor–Mediated Activation in.

MiR-146a Negatively Regulates TLR2-Induced Inflammatory Responses in Keratinocytes Florian Meisgen, Ning Xu Landén, Aoxue Wang, Bence Réthi, Charbel.

Inhibiting MDM2-p53 Interaction Suppresses Tumor Growth in Patient-Derived Non– Small Cell Lung Cancer Xenograft Models Josephine Hai, PhD, Shingo Sakashita,

Cyclin E1 Is Amplified and Overexpressed in Osteosarcoma

IQGAP1 and IQGAP3 Serve Individually Essential Roles in Normal Epidermal Homeostasis and Tumor Progression Christine L. Monteleon, Andrew McNeal, Elizabeth.

Interleukin-22 Is Frequently Expressed in Small- and Large-Cell Lung Cancer and Promotes Growth in Chemotherapy-Resistant Cancer Cells Sebastian Kobold,

The Human Immunodeficiency Virus Protease Inhibitor Ritonavir Inhibits Lung Cancer Cells, in Part, by Inhibition of Survivin Anjaiah Srirangam, PhD,

Volume 25, Issue 3, Pages (March 2017)

MicroRNA-101 Exerts Tumor-Suppressive Functions in Non-small Cell Lung Cancer through Directly Targeting Enhancer of Zeste Homolog 2 Ji-guang Zhang,

Kelsie L. Thu, BSc, Raj Chari, PhD, William W

PD-L1 Is Upregulated by Simultaneous Amplification of the PD-L1 and JAK2 Genes in Non–Small Cell Lung Cancer Seiichi Ikeda, MSc, Tatsuro Okamoto, MD,

G-Protein Coupled Receptor Family C, Group 5, Member A (gprc5a) Expression Is Decreased in the Adjacent Field and Normal Bronchial Epithelia of Patients.

Apelin Expression in Human Non-small Cell Lung Cancer: Role in Angiogenesis and Prognosis Judit Berta, MS, Istvan Kenessey, MD, Judit Dobos, PhD, Jozsef.

A Novel Approach to Detect Programed Death Ligand 1 (PD-L1) Status and Multiple Tumor Mutations Using a Single Non–Small-Cell Lung Cancer (NSCLC) Bronchoscopy.

Christina I. Selinger, PhD, Wendy A

Role of Chromosome 3q Amplification in Lung Cancer

Gene Copy Number Aberrations Are Associated with Survival in Histologic Subgroups of Non-small Cell Lung Cancer Patrick Micke, MD, PhD, Karolina Edlund,

Mechanisms of Acquired Resistance to AZD9291

Nicotinamide Phosphoribosyltransferase: A Potent Therapeutic Target in Non-small Cell Lung Cancer with Epidermal Growth Factor Receptor-Gene Mutation

A Translational View of the Molecular Pathogenesis of Lung Cancer

Volume 29, Issue 5, Pages (May 2016)

Aberrant Regulation of the MRP3 Gene in Non-small Cell Lung Carcinoma

Use of MicroRNA Expression Levels to Predict Outcomes in Resected Stage I Non- small Cell Lung Cancer Eric Duncavage, MD, Boone Goodgame, MD, Ananth Sezhiyan,

Ly6/uPAR-Related Protein C4

Long Noncoding RNA BC as a Novel Therapeutic Target for Colorectal Cancer that Suppresses Metastasis by Upregulating TIMP3 Jiaxin Lin, Xin Tan,

Gefitinib Enhances Cytotoxicities of Antimicrotubule Agents in Non–Small-Cell Lung Cancer Cells Exhibiting No Sensitizing Epidermal Growth Factor Receptor.

MELK Promotes Melanoma Growth by Stimulating the NF-κB Pathway

Genetic Changes in Squamous Cell Lung Cancer: A Review

Marijn T.M. van Jaarsveld, Difan Deng, Erik A.C. Wiemer, Zhike Zi

Elevated Expression of BIRC6 Protein in Non–Small-Cell Lung Cancers is Associated with Cancer Recurrence and Chemoresistance Xin Dong, MD, Dong Lin,

Phosphorylation of CBP by IKKα Promotes Cell Growth by Switching the Binding Preference of CBP from p53 to NF-κB Wei-Chien Huang, Tsai-Kai Ju, Mien-Chie.

Genome-wide Functional Analysis Reveals Factors Needed at the Transition Steps of Induced Reprogramming Chao-Shun Yang, Kung-Yen Chang, Tariq M. Rana

Proteomic Profiling Identifies Pathways Dysregulated in Non-small Cell Lung Cancer and an Inverse Association of AMPK and Adhesion Pathways with Recurrence

Presentation transcript:

Genetic Disruption of KEAP1/CUL3 E3 Ubiquitin Ligase Complex Components is a Key Mechanism of NF-KappaB Pathway Activation in Lung Cancer Kelsie L. Thu, BSc, Larissa A. Pikor, BSc, Raj Chari, PhD, Ian M. Wilson, PhD, Calum E. MacAulay, PhD, John C. English, MD, Ming- Sound Tsao, MD, Adi F. Gazdar, MD, Stephen Lam, MD, Wan L. Lam, PhD, William W. Lockwood, PhD Journal of Thoracic Oncology Volume 6, Issue 9, Pages 1521-1529 (September 2011) DOI: 10.1097/JTO.0b013e3182289479 Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 The KEAP1 Cullin-3 E3-ubiquitin ligase complex and its roles in maintaining cellular levels of NRF2 and IKBKB. A, When complex components are intact, KEAP1 facilitates binding of NRF2 or IKBKB, which promotes their ubiquitination. This complex prevents accumulation of IKBKB and subsequent NF-κB activation. B, Disruption of any complex component compromises function leading to stabilization and accumulation of IKBKB and aberrant activation of NF-κB. Journal of Thoracic Oncology 2011 6, 1521-1529DOI: (10.1097/JTO.0b013e3182289479) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 Frequent disruption of the KEAP1 E3-ligase complex components and IKBKB in non-small cell lung cancer (NSCLC). A, Summary of DNA copy number and gene expression alterations in NSCLC tumors. B, Copy number analysis of 261 lung tumors revealed frequent loss of KEAP1, RBX1, and CUL3 and frequent gain of IKBKB. Vertical columns indicate individual tumor samples, and only samples with ≥1 alterations are shown. C, Messenger RNA (mRNA) expression profiles for 48 lung tumors revealed frequent underexpression of complex components and overexpression of IKBKB. Expression was considered altered if tumor/matched nonmalignant tissue was changed more than twofold. D, KEAP1, CUL3, and IKBKB exhibit statistically significant differences in copy number alteration patterns between adenocarcinoma (AC) and squamous cell carcinoma (SCC) (Fisher's exact test, p < 0.01). Journal of Thoracic Oncology 2011 6, 1521-1529DOI: (10.1097/JTO.0b013e3182289479) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 IKBKB protein expression in non-small cell lung cancer (NSCLC). A, Western blot depicting IKBKB protein expression in eight cell lines with varying degrees of genetic disruption to KEAP1 E3-ligase complex components and/or IKBKB (as determined from copy number profiles of 90 NSCLC cell lines). Nonmalignant human bronchial epithelial (NHBE) lung line provides a baseline for IKBKB expression. The number of disrupted genes for each line is indicated above the cell line. B, qPCR assessment of mRNA expression levels for KEAP1, RBX1, and CUL3 after siRNA-mediated knockdown relative to a nontargeting control (siNTC). Error bars represent the standard error in relative expression across all biological replicates. C, Western blot depicting the effects of transient siRNA knockdown of KEAP1, RBX1, and CUL3, on total and phospho-IKBKB and NF-κB protein levels. Journal of Thoracic Oncology 2011 6, 1521-1529DOI: (10.1097/JTO.0b013e3182289479) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 Activation of NF-κB targets in tumors with aberrant expression of KEAP1 E3-ligase complex components and/or IKBKB. A–D, Box and whisker plots demonstrating four examples of NF-κB target genes (BCL2L11, CXCL13, MMP9, and TRAF1) that are significantly up-regulated in tumors with underexpression of KEAP1, RBX1, and/or CUL3 or overexpression of IKBKB, relative to matched nonmalignant lung tissues (Wilcoxon sign rank test, p ≤ 0.001). Copy number status of the NF-κB target gene loci was determined in these tumors to ensure that overexpression was not due to dosage changes of the target genes. Journal of Thoracic Oncology 2011 6, 1521-1529DOI: (10.1097/JTO.0b013e3182289479) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 5 Pharmacological inhibition of IKBKB in non-small cell lung cancer (NSCLC) cells. Alamar blue cell viability assays were performed to measure the effect of IKBKB inhibition by a cell permeable, competitive ATP inhibitor, IKK-2 inhibitor IV on five NSCLC cell lines. H2122, H23, H3255, and HCC95 harbored genetic alterations to either IKBKB or one or more of the KEAP1 E3-ligase complex components, whereas H1650 was not altered at the DNA level. Journal of Thoracic Oncology 2011 6, 1521-1529DOI: (10.1097/JTO.0b013e3182289479) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions