Choline kinase as a link connecting phospholipid metabolism and cell cycle regulation: implications in cancer therapy.

Choline kinase alpha (ChoKalpha) is an enzyme involved in the metabolism of phospholipids recently found to play a relevant role in the regulation of cell proliferation, oncogenic transformation and human carcinogenesis. In addition, this novel oncogene has been recently defined as a prognostic factor in human cancer, and as a promising target for therapy since its specific inhibitors display efficient antitumoral activity in vivo. However, the mechanism by which this enzyme is involved in the regulation of these processes is not yet understood. Using differential microarray analysis, we identify target genes that provide the basis for the understanding of the molecular mechanism for the regulation of cell proliferation and transformation mediated by over-expression of the human ChoKalpha. These results fully support a critical role of this enzyme in the regulation of the G1-->S transition at different levels, and its relevant role in human carcinogenesis. The molecular basis to understand the connection between phospholipids metabolism and cell cycle regulation through choline kinase is reported.

[1]  A. Depaoli-Roach,et al.  Cyclin G2 Associates with Protein Phosphatase 2A Catalytic and Regulatory B′ Subunits in Active Complexes and Induces Nuclear Aberrations and a G1/S Phase Cell Cycle Arrest* , 2002, The Journal of Biological Chemistry.

[2]  A. Sparreboom,et al.  Modulation of cytochrome P450 activity: implications for cancer therapy. , 2005, The Lancet. Oncology.

[3]  J. Griffiths,et al.  Noninvasive magnetic resonance spectroscopic pharmacodynamic markers of the choline kinase inhibitor MN58b in human carcinoma models. , 2006, Cancer research.

[4]  Tim A D Smith,et al.  [Methyl-3H]-choline incorporation into MCF-7 cells: correlation with proliferation, choline kinase and phospholipase D assay. , 2007, Anticancer research.

[5]  H. Degani,et al.  Phosphocholine as a biomarker of breast cancer: Molecular and biochemical studies , 2007, International journal of cancer.

[6]  Chao Lu,et al.  Improving the scaling normalization for high-density oligonucleotide GeneChip expression microarrays , 2004, BMC Bioinformatics.

[7]  R. Hipskind,et al.  Oct-1 Potentiates CREB-Driven Cyclin D1 Promoter Activation via a Phospho-CREB- and CREB Binding Protein-Independent Mechanism , 2002, Molecular and Cellular Biology.

[8]  C. Rasmussen,et al.  Calmodulin-dependent protein kinase II is required for G1/S progression in HeLa cells. , 1995, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[9]  A. Means,et al.  Regulation of Cyclin D1/Cdk4 Complexes by Calcium/Calmodulin-dependent Protein Kinase I* , 2004, Journal of Biological Chemistry.

[10]  K. Jöckel,et al.  Software packages for quantitative microarray-based gene expression analysis. , 2003, Current pharmaceutical biotechnology.

[11]  Denis Vivien,et al.  Direct binding of Smad3 and Smad4 to critical TGFβ‐inducible elements in the promoter of human plasminogen activator inhibitor‐type 1 gene , 1998, The EMBO journal.

[12]  S. Rose.  Transformed cells. , 1949, Scientific American.

[13]  J. Lacal,et al.  Regulation of choline kinase activity by Ras proteins involves Ral–GDS and PI3K , 2002, Oncogene.

[14]  S. Milstien,et al.  Targeting sphingosine-1-phosphate: a novel avenue for cancer therapeutics. , 2006, Cancer cell.

[15]  J. Lacal.  Choline kinase: a novel target for antitumor drugs. , 2001, IDrugs : the investigational drugs journal.

[16]  J. Lacal,et al.  Inhibition of choline kinase as a specific cytotoxic strategy in oncogene-transformed cells , 2003, Oncogene.

[17]  R. Medzhitov,et al.  Inducible Activation of TLR4 Confers Resistance to Hyperoxia-Induced Pulmonary Apoptosis , 2006, The Journal of Immunology.

[18]  Yusuf A. Hannun,et al.  Biologically active sphingolipids in cancer pathogenesis and treatment , 2004, Nature Reviews Cancer.

[19]  Lacal Jc.  Choline kinase: a novel target for antitumor drugs. , 2001 .

[20]  Y. Yonekura,et al.  Radiolabeled choline as a proliferation marker: comparison with radiolabeled acetate. , 2004, Nuclear medicine and biology.

[21]  A. Lykidis,et al.  Regulation of mammalian cell membrane biosynthesis. , 2001, Progress in nucleic acid research and molecular biology.

[22]  A. Iavarone,et al.  Kip/Cip and Ink4 Cdk inhibitors cooperate to induce cell cycle arrest in response to TGF-beta. , 1995, Genes & development.

[23]  A. Ramírez de Molina,et al.  Generation and characterization of monoclonal antibodies against choline kinase alpha and their potential use as diagnostic tools in cancer. , 2006, International journal of oncology.

[24]  K. Nakayama,et al.  p107 inhibits G1 to S phase progression by down-regulating expression of the F-box protein Skp2 , 2005, The Journal of cell biology.

[25]  J. Massagué,et al.  TGFβ Signaling in Growth Control, Cancer, and Heritable Disorders , 2000, Cell.

[26]  M. Lan,et al.  IA-2, a transmembrane protein tyrosine phosphatase, is expressed in human lung cancer cell lines with neuroendocrine phenotype. , 1996, Cancer Research.

[27]  Z. Bhujwalla,et al.  Molecular Causes of the Aberrant Choline Phospholipid Metabolism in Breast Cancer , 2004, Cancer Research.

[28]  J. Massagué,et al.  TGFbeta signaling in growth control, cancer, and heritable disorders. , 2000, Cell.

[29]  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.

[30]  J. Lacal,et al.  In vivo antitumor activity of choline kinase inhibitors: a novel target for anticancer drug discovery. , 1999, Cancer research.

[31]  Jose M. Silva,et al.  Increased choline kinase activity in human breast carcinomas: clinical evidence for a potential novel antitumor strategy , 2002, Oncogene.

[32]  A. Carrera,et al.  Control of Cyclin G2 mRNA Expression by Forkhead Transcription Factors: Novel Mechanism for Cell Cycle Control by Phosphoinositide 3-Kinase and Forkhead , 2004, Molecular and Cellular Biology.

[33]  D. Wong,et al.  Cyclin G2 Dysregulation in Human Oral Cancer , 2004, Cancer Research.

[34]  Alicia Oshlack,et al.  Normalization of boutique two-color microarrays with a high proportion of differentially expressed probes , 2007, Genome Biology.

[35]  R. Kolesnick,et al.  Ceramide and sphingosine 1-phosphate in anti-cancer therapies. , 2003, Cancer treatment and research.

[36]  Marcin Skrzypski,et al.  Expression of choline kinase alpha to predict outcome in patients with early-stage non-small-cell lung cancer: a retrospective study. , 2007, The Lancet. Oncology.

[37]  S. Canevari,et al.  Alterations of choline phospholipid metabolism in ovarian tumor progression. , 2005, Cancer research.

[38]  H. Duan,et al.  Oct transcription factors mediate t(14;18) lymphoma cell survival by directly regulating bcl-2 expression , 2006, Oncogene.

[39]  D. Megías,et al.  Choline Kinase Activation Is a Critical Requirement for the Proliferation of Primary Human Mammary Epithelial Cells and Breast Tumor Progression , 2004, Cancer Research.

[40]  Z. Bhujwalla,et al.  Choline kinase alpha in cancer prognosis and treatment. , 2007, The Lancet. Oncology.

[41]  V. Raman,et al.  RNA interference-mediated choline kinase suppression in breast cancer cells induces differentiation and reduces proliferation. , 2005, Cancer research.

[42]  Roland Eils,et al.  Translating Expression Profiling into a Clinically Feasible Test to Predict Neuroblastoma Outcome , 2007, Clinical Cancer Research.

[43]  David Gallego-Ortega,et al.  Choline kinase is a novel oncogene that potentiates RhoA-induced carcinogenesis. , 2005, Cancer research.

[44]  A. Labarga,et al.  A gene signature of 8 genes could identify the risk of recurrence and progression in Dukes' B colon cancer patients. , 2007, Oncology reports.

[45]  G. Martin,et al.  Cell signaling and cancer. , 2003, Cancer cell.

[46]  R. Rosell,et al.  Overexpression of choline kinase is a frequent feature in human tumor-derived cell lines and in lung, prostate, and colorectal human cancers. , 2002, Biochemical and biophysical research communications.

[47]  M. Noble,et al.  Reversal of Growth Suppression by p107 via Direct Phosphorylation by Cyclin D1/Cyclin-Dependent Kinase 4 , 2002, Molecular and Cellular Biology.

[48]  E. Alexander,et al.  Choline, an essential nutrient for humans. , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[49]  I. Dusanter-Fourt,et al.  STAT5 and Oct-1 Form a Stable Complex That Modulates Cyclin D1 Expression , 2003, Molecular and Cellular Biology.

[50]  Gavin Sherlock,et al.  Clustering microarray data. , 2006, Methods in enzymology.

[51]  E. Bandrés,et al.  Differential expression of Rac1 identifies its target genes and its contribution to progression of colorectal cancer. , 2007, The international journal of biochemistry & cell biology.

[52]  V. Raman,et al.  Choline kinase down-regulation increases the effect of 5-fluorouracil in breast cancer cells. , 2007, Cancer research.

[53]  J. Lacal,et al.  Choline kinase inhibition induces the increase in ceramides resulting in a highly specific and selective cytotoxic antitumoral strategy as a potential mechanism of action , 2004, Oncogene.