title: Caveolae as a target to quench autoinduction of the metastatic phenotype in lung cancer.
abstract: OBJECTIVE
  Mevalonate pathway inhibitors are potentially useful chemotherapeutic agents showing growth inhibition and pro-apoptotic effects in cancer cells. The effects of statins and bisphosphonates on cancer growth are attributed to a reduction in protein isoprenylation. Post-translational modification and activation of GTPase binding Ras superfamily permit the recruitment of these signal proteins to membranes where they mediate the cancer phenotype. Here, the effects of three inhibitors of the mevalonate pathway and one specific inhibitor of sterol regulatory element-binding proteins were studied in both an ER-negative, Ras-inactive breast (MDA-MB-231) and lung adenocarcinoma (CaLu-1) cells in vitro.
  
  
  METHODS
  Treated cells were subject to genome-wide gene expression profiling. A gene subset was established so that the epithelial to mesenchymal transition (EMT) could be observed and compared with signalling protein shifts.
  
  
  RESULTS
  Within the subset, some genes normally up-regulated during EMT were asymmetrically reduced by a Δ-24 DHCR inhibitor in the lung cells. Signalling proteins associated with caveolae were down-regulated by this oxidoreductase inhibitor, while those associated with membrane rafts were up-regulated.
  
  
  CONCLUSIONS
  This study decouples isoprenylation effects from cholesterol events per se. The data support a hypothesis that caveolae are abolished by Δ-24 DHCR intervention and it is revealed that these microdomains are vital EMT signalling structures for lung cells but not ER- and Ras-negative breast cells. When signalling by extracellular signals is quenched by removal of the hydrophilic conduit provided by caveolae, the transcriptome responds by moving the cellular identity towards quiescence.
authors.affiliation: Institute of Science Technology in Medicine, Keele University, Keele, Staffordshire, ST5 5BG, UK. d.j.garnett@keele.ac.uk.
authors.forename: David John
authors.initials: DJ
authors.lastname: Garnett
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary*; D000077192:Adenocarcinoma of Lung; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D021941:Caveolae / Q000187:drug effects* / Q000502:physiology; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology* / Q000556:secondary; D008798:Mevalonic Acid / Q000037:antagonists & inhibitors*; D009362:Neoplasm Metastasis; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors; D010641:Phenotype; D011335:Proadifen / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D051242:Caveolin 1; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009419:Nerve Tissue Proteins; D011335:Proadifen; D044925:Oxidoreductases Acting on CH-CH Group Donors; C499055:DHCR24 protein, human; D008798:Mevalonic Acid
keywords: Caveolae; Gene expression; Metastasis; Proadifen; Statins