CDK2 Inhibition Causes Anaphase Catastrophe in Lung Cancer through the Centrosomal Protein CP110.

Aneuploidy is frequently detected in human cancers and is implicated in carcinogenesis. Pharmacologic targeting of aneuploidy is an attractive therapeutic strategy, as this would preferentially eliminate malignant over normal cells. We previously discovered that CDK2 inhibition causes lung cancer cells with more than two centrosomes to undergo multipolar cell division leading to apoptosis, defined as anaphase catastrophe. Cells with activating KRAS mutations were especially sensitive to CDK2 inhibition. Mechanisms of CDK2-mediated anaphase catastrophe and how activated KRAS enhances this effect were investigated. Live-cell imaging provided direct evidence that following CDK2 inhibition, lung cancer cells develop multipolar anaphase and undergo multipolar cell division with the resulting progeny apoptotic. The siRNA-mediated repression of the CDK2 target and centrosome protein CP110 induced anaphase catastrophe of lung cancer cells. In contrast, CP110 overexpression antagonized CDK2 inhibitor-mediated anaphase catastrophe. Furthermore, activated KRAS mutations sensitized lung cancer cells to CDK2 inhibition by deregulating CP110 expression. Thus, CP110 is a critical mediator of CDK2 inhibition-driven anaphase catastrophe. Independent examination of murine and human paired normal-malignant lung tissues revealed marked upregulation of CP110 in malignant versus normal lung. Human lung cancers with KRAS mutations had significantly lower CP110 expression as compared with KRAS wild-type cancers. Thus, a direct link was found between CP110 and CDK2 inhibitor antineoplastic response. CP110 plays a mechanistic role in response of lung cancer cells to CDK2 inhibition, especially in the presence of activated KRAS mutations.

[1]  M. Pagano,et al.  USP33 regulates centrosome biogenesis via deubiquitination of the centriolar protein CP110 , 2013, Nature.

[2]  T. Stinchcombe,et al.  KRAS mutation: should we test for it, and does it matter? , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  A. Gingras,et al.  Interaction Proteomics Identify NEURL4 and the HECT E3 Ligase HERC2 as Novel Modulators of Centrosome Architecture* , 2012, Molecular & Cellular Proteomics.

[4]  Neil J Ganem,et al.  DNA breaks and chromosome pulverization from errors in mitosis , 2012, Nature.

[5]  J. Palmer,et al.  Inflammation-mediated upregulation of centrosomal protein 110, a negative modulator of ciliogenesis, in patients with chronic rhinosinusitis. , 2011, The Journal of allergy and clinical immunology.

[6]  A. Balmain,et al.  Progressive Genomic Instability in the FVB/KrasLA2 Mouse Model of Lung Cancer , 2011, Molecular Cancer Research.

[7]  E. Dmitrovsky,et al.  Bexarotene Plus Erlotinib Suppress Lung Carcinogenesis Independent of KRAS Mutations in Two Clinical Trials and Transgenic Models , 2011, Cancer Prevention Research.

[8]  B. Dynlacht,et al.  Regulating the transition from centriole to basal body , 2011, The Journal of cell biology.

[9]  E. Dmitrovsky,et al.  Anaphase Catastrophe Is a Target for Cancer Therapy , 2011, Clinical Cancer Research.

[10]  M. Harrison,et al.  The G1 phase Cdks regulate the centrosome cycle and mediate oncogene-dependent centrosome amplification , 2011, Cell Division.

[11]  E. Raymond,et al.  Phase I evaluation of seliciclib (R-roscovitine), a novel oral cyclin-dependent kinase inhibitor, in patients with advanced malignancies. , 2010, European journal of cancer.

[12]  L. Chodosh,et al.  The Ras oncogene signals centrosome amplification in mammary epithelial cells through cyclin D1/Cdk4 and Nek2 , 2010, Oncogene.

[13]  M. Pagano,et al.  SCFCyclin F controls centrosome homeostasis and mitotic fidelity via CP110 degradation , 2010, Nature.

[14]  E. Dmitrovsky,et al.  Targeting the Cyclin E-Cdk-2 Complex Represses Lung Cancer Growth by Triggering Anaphase Catastrophe , 2010, Clinical Cancer Research.

[15]  M. Pagano,et al.  SCFCyclin F controls centrosome homeostasis and mitotic fidelity through CP 110 degradation , 2010 .

[16]  E. Nigg,et al.  Control of Centriole Length by CPAP and CP110 , 2009, Current Biology.

[17]  David Pellman,et al.  A Mechanism Linking Extra Centrosomes to Chromosomal Instability , 2009, Nature.

[18]  M. Korc,et al.  Pancreatic cancer and precursor pancreatic intraepithelial neoplasia lesions are devoid of primary cilia. , 2009, Cancer research.

[19]  D. Pellman,et al.  Mechanisms to suppress multipolar divisions in cancer cells with extra centrosomes. , 2008, Genes & development.

[20]  V. Malhotra,et al.  CP110 suppresses primary cilia formation through its interaction with CEP290, a protein deficient in human ciliary disease. , 2008, Developmental cell.

[21]  E. Golemis,et al.  Cell cycle-dependent ciliogenesis and cancer. , 2008, Cancer research.

[22]  S. Kitareewan,et al.  Cyclin degradation for cancer therapy and chemoprevention , 2007, Journal of cellular biochemistry.

[23]  A. Spektor,et al.  Cep97 and CP110 Suppress a Cilia Assembly Program , 2007, Cell.

[24]  E. Dmitrovsky,et al.  Transgenic cyclin E triggers dysplasia and multiple pulmonary adenocarcinomas , 2007, Proceedings of the National Academy of Sciences.

[25]  Laurie A. Smith,et al.  Long-lasting arrest of murine polycystic kidney disease with CDK inhibitor roscovitine , 2006, Nature.

[26]  J. Minna,et al.  High expression of ligands for chemokine receptor CXCR2 in alveolar epithelial neoplasia induced by oncogenic kras. , 2006, Cancer research.

[27]  Brian David Dynlacht,et al.  CP110 cooperates with two calcium-binding proteins to regulate cytokinesis and genome stability. , 2006, Molecular biology of the cell.

[28]  B. Yoder,et al.  The primary cilium in cell signaling and cancer. , 2006, Cancer research.

[29]  P. Castagnola,et al.  Mutant KRAS, chromosomal instability and prognosis in colorectal cancer. , 2005, Biochimica et biophysica acta.

[30]  E. Dmitrovsky,et al.  A novel retinoic acid receptor beta isoform and retinoid resistance in lung carcinogenesis. , 2005, Journal of the National Cancer Institute.

[31]  M. Hafner,et al.  Centrosome aberrations in chronic myeloid leukemia correlate with stage of disease and chromosomal instability , 2005, Leukemia.

[32]  B. Clurman,et al.  Cyclin E in normal and neoplastic cell cycles , 2005, Oncogene.

[33]  E. Dmitrovsky,et al.  Involvement of UBE1L in ISG15 Conjugation during Retinoid-induced Differentiation of Acute Promyelocytic Leukemia* , 2004, Journal of Biological Chemistry.

[34]  F. Stivala,et al.  Amplified Centrosomes in Breast Cancer: A Potential Indicator of Tumor Aggressiveness , 2002, Breast Cancer Research and Treatment.

[35]  G. Pihan,et al.  Centrosome abnormalities and chromosome instability occur together in pre-invasive carcinomas. , 2003, Cancer research.

[36]  Vahan B. Indjeian,et al.  CP110, a cell cycle-dependent CDK substrate, regulates centrosome duplication in human cells. , 2002, Developmental cell.

[37]  H. Naiki,et al.  Prognostic significance of cyclin E overexpression in resected non-small cell lung cancer. , 2000, Cancer research.

[38]  W. Lingle,et al.  Altered centrosome structure is associated with abnormal mitoses in human breast tumors. , 1999, The American journal of pathology.

[39]  Carissa A. Sanchez,et al.  Formation of the tetraploid intermediate is associated with the development of cells with more than four centrioles in the elastase-simian virus 40 tumor antigen transgenic mouse model of pancreatic cancer. , 1991, Proceedings of the National Academy of Sciences of the United States of America.