title: Phosphorylated tubulin adaptor protein CRMP-2 as prognostic marker and candidate therapeutic target for NSCLC.
abstract: Collapsin response mediator protein-2 (CRMP-2) is the first described and most studied member of a family of proteins that mediate the addition of tubulin dimers to the growing microtubule. CRMPs have mainly been studied in the nervous system, but recently, they have been described in other tissues where they participate in vesicle transport, migration and mitosis. In this work, we aimed at studying the role of CRMP-2 in lung cancer cell division. We first explored the expression of CRMP-2 and phosphorylated (Thr 514) CRMP-2 in 91 samples obtained from patients with localized nonsmall cell lung cancer. We observed a significant correlation between high levels of nuclear phosphorylated CRMP-2 and poor prognosis in those patients. Interestingly, this association was only positive for untreated patients. To provide a mechanistic explanation to these findings, we used in vitro models to analyze the role of CRMP-2 and its phosphorylated forms in cell division. Thus, we observed by confocal microscopy and immunoprecipitation assays that CRMP-2 differentially colocalizes with the mitotic spindle during cell division. The use of phosphodefective or phosphomimetic mutants of CRMP-2 allowed us to prove that anomalies in the phosphorylation status of CRMP-2 result in changes in the mitotic tempo, and increments in the number of multinucleated cells. Finally, here we demonstrate that CRMP-2 phosphorylation impairment, or silencing induces p53 expression and promotes apoptosis through caspase 3 activation. These results pointed to CRMP-2 phosphorylation as a prognostic marker and potential new target to be explored in cancer therapy.
authors.affiliation: Oncology Division, Center for Applied Medical Research (CIMA), University of Navarra, 55 Pamplona, Spain.
authors.forename: Erik
authors.initials: E
authors.lastname: Oliemuller
authors.forename: Rafael
authors.initials: R
authors.lastname: Peláez
authors.forename: Saray
authors.initials: S
authors.lastname: Garasa
authors.forename: María J
authors.initials: MJ
authors.lastname: Pajares
authors.forename: Jackeline
authors.initials: J
authors.lastname: Agorreta
authors.forename: Rubén
authors.initials: R
authors.lastname: Pío
authors.forename: Luis M
authors.initials: LM
authors.lastname: Montuenga
authors.forename: Alvaro
authors.initials: A
authors.lastname: Teijeira
authors.forename: Susana
authors.initials: S
authors.lastname: Llanos
authors.forename: Ana
authors.initials: A
authors.lastname: Rouzaut
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000097:blood*; D015153:Blotting, Western; D018196:Carcinoma, Adenosquamous / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D018287:Carcinoma, Large Cell / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D002453:Cell Cycle; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008297:Male; D008870:Microtubules / Q000378:metabolism; D008875:Middle Aged; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics; D009367:Neoplasm Staging; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011379:Prognosis; D034741:RNA, Small Interfering / Q000235:genetics; D008941:Spindle Apparatus; D015996:Survival Rate; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; C095114:collapsin response mediator protein-2