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.

Collapsin response mediator proteins: Potential diagnostic and prognostic biomarkers in cancers (Review)

“…Such results are similar to those described in the colorectal carcinoma study by Wu et al (43). While, a significant correlation was identified between the high levels of phosphorylated CRMP2 (Thr-514) and shorter overall survival in the study by Oliemuller et al (44). However, the correlation between high levels of phosphorylated CRMP2 expression and poor overall survival was only demonstrated in patients who did not receive adjuvant therapy.…”

“…An additional study by Oliemuller et al investigated the protein expression of CRMP2 in 91 NSCLC patients (44). The authors identified that CRMP2 was expressed in the cytoplasm of normal and tumor tissues, with a higher expression exhibited in tumor tissues than in normal tissues.…”

A novel mouse model for the identification of thioredoxin-1 protein interactions

“…Although Crmp2 has been primarily associated with neurological diseases including Alzheimer’s and schizophrenia [47–50], Crmp2 is highly expressed in lung tissue as well as lung tumor cells [51]. Although endogenous function of Crmp2 in the lung remains unknown, differential Crmp2 posttranslational modifications are associated with nonsmall cell lung cancer [52]. The detection of known Trx1 substrates in this transgenic mouse model demonstrates the functionality of our Trx1 substrate trap mouse and our results are the first evidence that Trx1 interacts with Crmp2 in the lung in vivo.…”

Upregulation of CRMP4, a new prostate cancer metastasis suppressor gene, inhibits tumor growth in a nude mouse intratibial injection model

“…Both GSK-3β and WAVE-1 were involved in CRMP mediated axon outgrowth, indicating CRMP has diverse functions in different cellular processes. Other CRMP family members involved in cancer include CRMP2, CRMP4 and CRMP5, all were reported associated with different cancer cell migration, invasion, differentiation and clinical outcome in certain tumor types (16)(17)(18)(19). In our previous study (20), we first identified CRMP4 as a prostate cancer metastasis suppressor factor by proteomics approach and verified that CRMP4 suppress prostate cancer cell line proliferation and invasion in vitro and the downregulation of CRMP4 in metastatic tumor may be due to the methylation of the CpG island within the promoter region of the CRMP4 gene.…”