RGS 16 , a novel p 53 and pRb cross-talk candidate inhibits migration and invasion of pancreatic cancer cells

Data collected since the discovery of p53 and pRb/RB1 suggests these tumor suppressors cooperate to inhibit tumor progression. Patients who have mutations in both p53 and RB1 genes have increased tumor reoccurrence and decreased survival compared to patients with only one tumor suppressor gene inactivated. It remains unclear how p53 and pRb cooperate toward inhibiting tumorigenesis. Using RNA expression profiling we identified 179 p53 and pRb cross-talk candidates in normal lung fibroblasts (WI38) cells exogenously coexpressing p53 and pRb. Regulator of G protein signaling 16 (RGS16) was among the p53 and pRb cross-talk candidates and has been implicated in inhibiting activation of several oncogenic pathways associated with proliferation, migration, and invasion of cancer cells. RGS16 has been found to be downregulated in pancreatic cancer patients with metastases compared to patients without metastasis. Expression of RGS16 mRNA was decreased in the pancreatic cancer cell lines tested compared to control. Expression of RGS16 inhibited migration of the BxPC-3 and AsPC-1 but not PANC-1 cells and inhibited invasion of BxPC-3 and AsPC-1 cells with no impact on cell viability. We have identified for the first time p53 and pRb cross-talk candidates and a role for RGS16 to inhibit pancreatic cancer migration and invasion.

[1]  O. Mian,et al.  Management Options in Locally Advanced Pancreatic Cancer , 2014, Current Oncology Reports.

[2]  N. Taira,et al.  Induction of amphiregulin by p53 promotes apoptosis via control of microRNA biogenesis in response to DNA damage , 2013, Proceedings of the National Academy of Sciences.

[3]  M. Atkins,et al.  Treatment of BRAF‐Mutant Melanoma: The Role of Vemurafenib and Other Therapies , 2013, Clinical pharmacology and therapeutics.

[4]  S. Godár,et al.  Rb Suppresses Collective Invasion, Circulation and Metastasis of Breast Cancer Cells in CD44-Dependent Manner , 2013, PloS one.

[5]  Hiromu Suzuki,et al.  AKR1B10, a Transcriptional Target of p53, Is Downregulated in Colorectal Cancers Associated with Poor Prognosis , 2013, Molecular Cancer Research.

[6]  D. Schlessinger,et al.  T antigen transformation reveals Tp53/RB-dependent route to PLAC1 transcription activation in primary fibroblasts , 2013, Oncogenesis.

[7]  S. Oesterreich,et al.  Crosstalk between lysine-specific demethylase 1 (LSD1) and histone deacetylases mediates antineoplastic efficacy of HDAC inhibitors in human breast cancer cells. , 2013, Carcinogenesis.

[8]  B. Ogretmen,et al.  Folate Stress Induces Apoptosis via p53-dependent de Novo Ceramide Synthesis and Up-regulation of Ceramide Synthase 6* , 2013, The Journal of Biological Chemistry.

[9]  Jens T Siveke,et al.  EGF receptor is required for KRAS-induced pancreatic tumorigenesis. , 2012, Cancer cell.

[10]  Zhihui Xie,et al.  RGS16 Attenuates Pulmonary Th2/Th17 Inflammatory Responses , 2012, The Journal of Immunology.

[11]  P. Claudio,et al.  Targeting a Newly Established Spontaneous Feline Fibrosarcoma Cell Line by Gene Transfer , 2012, PloS one.

[12]  S. Sebti,et al.  Regulation of matrix metalloproteinase genes by E2F transcription factors: Rb-Raf-1 interaction as a novel target for metastatic disease. , 2012, Cancer research.

[13]  Jean Y. J. Wang,et al.  RB restricts DNA damage-initiated tumorigenesis through an LXCXE-dependent mechanism of transcriptional control. , 2011, Molecular cell.

[14]  B. Foster,et al.  E2f binding-deficient Rb1 protein suppresses prostate tumor progression in vivo , 2010, Proceedings of the National Academy of Sciences.

[15]  David S. Park,et al.  Rb/E2F Regulates Expression of Neogenin during Neuronal Migration , 2010, Molecular and Cellular Biology.

[16]  M. Ouellette,et al.  Expression of oncogenic K‐ras and loss of Smad4 cooperate to induce the expression of EGFR and to promote invasion of immortalized human pancreas ductal cells , 2010, International journal of cancer.

[17]  Yoshio Miki,et al.  D4S234E, a novel p53-responsive gene, induces apoptosis in response to DNA damage. , 2010, Experimental cell research.

[18]  Douglas M. Yau,et al.  Non-canonical functions of RGS proteins. , 2010, Cellular signalling.

[19]  S. Choi,et al.  RGS16 and FosB underexpressed in pancreatic cancer with lymph node metastasis promote tumor progression , 2010, Tumor Biology.

[20]  Beverly A. Teicher,et al.  CXCL12 (SDF-1)/CXCR4 Pathway in Cancer , 2010, Clinical Cancer Research.

[21]  A. Levine,et al.  Differential levels of transcription of p53‐regulated genes by the arginine/proline polymorphism: p53 with arginine at codon 72 favors apoptosis , 2010, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[22]  J. Shea,et al.  Phenotype and Genotype of Pancreatic Cancer Cell Lines , 2010, Pancreas.

[23]  P. Fisher,et al.  Eradication of therapy-resistant human prostate tumors using an ultrasound-guided site-specific cancer terminator virus delivery approach. , 2010, Molecular therapy : the journal of the American Society of Gene Therapy.

[24]  L. Montanaro,et al.  The p53‐mediated sensitivity of cancer cells to chemotherapeutic agents is conditioned by the status of the retinoblastoma protein , 2009, The Journal of pathology.

[25]  D. Ginsberg,et al.  p53 and E2f: partners in life and death , 2009, Nature Reviews Cancer.

[26]  W. Hait,et al.  A role for p53 in the regulation of extracellular matrix metalloproteinase inducer in human cancer cells , 2009, Cancer biology & therapy.

[27]  H. Ishii,et al.  RGS16 Is a Marker for Prognosis in Colorectal Cancer , 2009, Annals of Surgical Oncology.

[28]  J. Toguchida,et al.  Molecular genetics of sarcomas: Applications to diagnoses and therapy , 2009, Cancer science.

[29]  Zhihui Xie,et al.  RGS16 Inhibits Breast Cancer Cell Growth by Mitigating Phosphatidylinositol 3-Kinase Signaling* , 2009, The Journal of Biological Chemistry.

[30]  L. Hansen,et al.  A fragile site within the HPC1 region at 1q25.3 affecting RGS16, RGSL1, and RGSL2 in human breast carcinomas , 2008, Genes, chromosomes & cancer.

[31]  Sheng-Chieh Hsu,et al.  Epidermal growth factor receptor cooperates with signal transducer and activator of transcription 3 to induce epithelial-mesenchymal transition in cancer cells via up-regulation of TWIST gene expression. , 2007, Cancer research.

[32]  Å. Borg,et al.  Tiling resolution array comparative genomic hybridization, expression and methylation analyses of dup(1q) in Burkitt lymphomas and pediatric high hyperdiploid acute lymphoblastic leukemias reveal clustered near-centromeric breakpoints and overexpression of genes in 1q22-32.3. , 2007, Human molecular genetics.

[33]  David Sidransky,et al.  A p53-type response element in the GDF15 promoter confers high specificity for p53 activation. , 2007, Biochemical and biophysical research communications.

[34]  J. Gutkind,et al.  G-protein-coupled receptors and cancer , 2007, Nature Reviews Cancer.

[35]  Michael A. Dyer,et al.  Inactivation of the p53 pathway in retinoblastoma , 2006, Nature.

[36]  K. Coombes,et al.  Identification of Cell Cycle Regulatory Genes as Principal Targets of p53-mediated Transcriptional Repression* , 2006, Journal of Biological Chemistry.

[37]  P. Claudio,et al.  Cell cycle control and beyond: emerging roles for the retinoblastoma gene family , 2006, Oncogene.

[38]  David C. Corney,et al.  Synergy of p53 and Rb deficiency in a conditional mouse model for metastatic prostate cancer. , 2006, Cancer research.

[39]  A. Giaccia,et al.  Genome-Wide Analysis of p53 under Hypoxic Conditions , 2006, Molecular and Cellular Biology.

[40]  Pierre Roux,et al.  Control of cell migration: a tumour suppressor function for p53? , 2006, Biology of the cell.

[41]  Shadan Ali,et al.  Simultaneous targeting of the epidermal growth factor receptor and cyclooxygenase-2 pathways for pancreatic cancer therapy , 2005, Molecular Cancer Therapeutics.

[42]  W. Vainchenker,et al.  RGS16 is a negative regulator of SDF-1-CXCR4 signaling in megakaryocytes. , 2005, Blood.

[43]  D. Bowtell,et al.  The retinoid anticancer signal: mechanisms of target gene regulation , 2005, British Journal of Cancer.

[44]  S. Bilodeau,et al.  Rb Enhances p160/SRC Coactivator-dependent Activity of Nuclear Receptors and Hormone Responsiveness* , 2005, Journal of Biological Chemistry.

[45]  P. Allavena,et al.  Increased Survival, Proliferation, and Migration in Metastatic Human Pancreatic Tumor Cells Expressing Functional CXCR4 , 2004, Cancer Research.

[46]  M. Oshimura,et al.  PI3K-Akt pathway: Its functions and alterations in human cancer , 2004, Apoptosis.

[47]  Jacek Bielawski,et al.  Role for Mammalian Neutral Sphingomyelinase 2 in Confluence-induced Growth Arrest of MCF7 Cells* , 2004, Journal of Biological Chemistry.

[48]  L. Beckett,et al.  Incidence, mechanism and prognostic value of activated AKT in pancreas cancer , 2003, British Journal of Cancer.

[49]  Kristian Helin,et al.  Identification of Target Genes of the p16INK4A-pRB-E2F Pathway* , 2003, Journal of Biological Chemistry.

[50]  J. M. Webster,et al.  Role of Regulator of G Protein Signaling 16 in Inflammation- Induced T Lymphocyte Migration and Activation , 2003, The Journal of Immunology.

[51]  J. Weinstein,et al.  Impact of p53 knockout and topotecan treatment on gene expression profiles in human colon carcinoma cells: a pharmacogenomic study. , 2003, Cancer research.

[52]  S. Benchimol,et al.  Transcriptional repression mediated by the p53 tumour suppressor , 2003, Cell Death and Differentiation.

[53]  F. Wright,et al.  Gene expression profiling of isogenic cells with different TP53 gene dosage reveals numerous genes that are affected by TP53 dosage and identifies CSPG2 as a direct target of p53 , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[54]  Thomas Dittmar,et al.  Induction of cancer cell migration by epidermal growth factor is initiated by specific phosphorylation of tyrosine 1248 of c‐erbB‐2 receptor via epidermal growth factor receptor , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[55]  A. Giordano,et al.  The retinoblastoma family: twins or distant cousins? , 2002, Genome Biology.

[56]  F. McCormick,et al.  The RB and p53 pathways in cancer. , 2002, Cancer cell.

[57]  Goberdhan P Dimri,et al.  A Role for p53 in Maintaining and Establishing the Quiescence Growth Arrest in Human Cells* , 2002, The Journal of Biological Chemistry.

[58]  H. Ngan,et al.  pRb-expressing adenovirus Ad5-Rb attenuates the p53-induced apoptosis in cervical cancer cell lines. , 2001, European journal of cancer.

[59]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[60]  M. Tatsuta,et al.  Inhibition of epidermal growth factor-induced RhoA translocation and invasion of human pancreatic cancer cells by 3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors. , 2001, Cancer research.

[61]  G. Getz,et al.  DNA microarrays identification of primary and secondary target genes regulated by p53 , 2001, Oncogene.

[62]  Christine Brun,et al.  In silico prediction of protein-protein interactions in human macrophages , 2001, BMC Research Notes.

[63]  M. Tsao,et al.  Inhibition of phosphatidylinositide 3-kinase enhances gemcitabine-induced apoptosis in human pancreatic cancer cells. , 2000, Cancer research.

[64]  P. Guida,et al.  pRB and p107 have distinct effects when expressed in pRB-deficient tumor cells at physiologically relevant levels , 2000, Oncogene.

[65]  Peter Gierschik,et al.  Growth factor-dependent activation of the Ras-Raf-MEK-MAPK pathway in the human pancreatic carcinoma cell line PANC-1 carrying activated K-ras: implications for cell proliferation and cell migration , 2000, Oncogene.

[66]  D. Notterman,et al.  Analysis of p53-regulated gene expression patterns using oligonucleotide arrays. , 2000, Genes & development.

[67]  D. Yap,et al.  mdm2: a bridge over the two tumour suppressors, p53 and Rb , 1999, Oncogene.

[68]  H. Friess,et al.  The antiapoptotic decoy receptor TRID/TRAIL-R3 is a p53-regulated DNA damage-inducible gene that is overexpressed in primary tumors of the gastrointestinal tract , 1999, Oncogene.

[69]  Y. Sun,et al.  Human Metalloproteinase‐1 (Collagenase‐1) Is a Tumor Suppressor Protein p53 Target Gene , 1999, Annals of the New York Academy of Sciences.

[70]  Y. Sun,et al.  p53 Down-regulates Human Matrix Metalloproteinase-1 (Collagenase-1) Gene Expression* , 1999, The Journal of Biological Chemistry.

[71]  J. Barrett,et al.  Differential regulation of p21 by p53 and Rb in cellular response to oxidative stress , 1999, Molecular carcinogenesis.

[72]  Z. Su,et al.  The cancer growth suppressor gene mda-7 selectively induces apoptosis in human breast cancer cells and inhibits tumor growth in nude mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[73]  M. Cummings,et al.  Reduced expression of retinoblastoma gene product (pRB) and high expression of p53 are associated with poor prognosis in ovarian cancer , 1997, International journal of cancer.

[74]  S. Velasco-Miguel,et al.  The p53 tumor suppressor targets a novel regulator of G protein signaling. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[75]  C. Cordon-Cardo,et al.  Cooperative effects of p53 and pRB alterations in primary superficial bladder tumors. , 1997, Cancer research.

[76]  R. Berger,et al.  Identification of BTG2, an antiproliferative p53–dependent component of the DNA damage cellular response pathway , 1996, Nature Genetics.

[77]  R. Hruban,et al.  Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma , 1994, Nature Genetics.

[78]  P. Hall,et al.  Abnormalities of the p53 tumour suppressor gene in human pancreatic cancer , 1992, British Journal of Cancer.

[79]  Stephen H. Friend,et al.  A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma , 1986, Nature.

[80]  E. Diamandis,et al.  Pancreatic cancer. , 2013, Clinical chemistry.

[81]  Dihua Yu,et al.  Wild-type p53 inhibits nuclear factor-kappaB-induced matrix metalloproteinase-9 promoter activation: implications for soft tissue sarcoma growth and metastasis. , 2006, Molecular cancer research : MCR.

[82]  K. Druey,et al.  RGS16 inhibits signalling through the G alpha 13-Rho axis. , 2003, Nature cell biology.

[83]  R. Ralhan,et al.  Alterations in p53 and pRb pathways and their prognostic significance in oesophageal cancer. , 2002, European journal of cancer.

[84]  M. Farquhar,et al.  The regulator of G protein signaling family. , 2000, Annual review of pharmacology and toxicology.

[85]  W. Sellers,et al.  Stable binding to E2F is not required for the retinoblastoma protein to activate transcription, promote differentiation, and suppress tumor cell growth. , 1998, Genes & development.

[86]  R. DePinho,et al.  Tumorigenic and developmental effects of combined germ-line mutations in Rb and p53. , 1994, Cold Spring Harbor symposia on quantitative biology.

[87]  H. Friess,et al.  Coexpression of epidermal growth factor receptor and ligands in human pancreatic cancer is associated with enhanced tumor aggressiveness. , 1993, Anticancer research.

[88]  S. Akinaga,et al.  The P53 Tumour Suppressor Gene Regulates a Dna Damage-triggered G1 Checkpoint (hartwell and Kastan, 1994). P53-dependent Growth Arrest Occurs upon Transcriptional Activation of P21, Which in Turn Inhibits Cyclin-dependent Kinase-mediated Phosphorylation Of , 2022 .