Src kinases catalytic activity regulates proliferation, migration and invasiveness of MDA-MB-231 breast cancer cells

María Pilar Sánchez-Bailón, Annarica Calcabrini, Daniel Gómez-Domínguez, Beatriz Morte, Esther Martín-Forero, Gonzalo Gómez-López, Agnese Molinari, Kay Uwe Wagner, Jorge Martín-Pérez

Research output: Contribution to journalArticle

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Abstract

SFKs are frequently deregulated in cancer where they control cellular proliferation, migration, survival and metastasis. Here we study the role of SFKs catalytic activity in triple-negative/basal-like and metastatic human breast cancer MDA-MB-231 cells employing three well-established inhibitors: Dasatinib, PP2 and SU6656. These compounds inhibited migration and invasion. Concomitantly, they reduced Fak, paxillin, p130CAS, caveolin-1 phosphorylation and altered cytoskeletal structures. They also inhibited cell proliferation, but in different manners. Dasatinib and PP2 increased p27 Kip1 expression and reduced c-Myc levels, restraining G1-S transition. In contrast, SU6656 did not modify p27 Kip1 expression, slightly altered c-Myc levels and generated polyploid multinucleated cells, indicating inhibition of cytokinesis. These later effects were also observed in SYF fibroblasts, suggesting a SFKs-independent action. ZM447439, an Aurora B kinase inhibitor, produced similar cell cycle and morphological alterations in MDA-MB-231 cells, indicating that SU6656 blocked Aurora B kinase. This was confirmed by inhibition of histone H3 phosphorylation, the canonical Aurora B kinase substrate. Furthermore, hierarchical clustering analysis of gene expression profiles showed that SU6656 defined a set of genes that differed from Dasatinib and PP2. Additionally, Gene Set Enrichment Analyses revealed that SU6656 significantly reduces the Src pathway. Together, these results show the importance of SFKs catalytic activity for MDA-MB-231 proliferation, migration and invasiveness. They also illustrate that SU6656 acts as dual SFKs and Aurora B kinase inhibitor, suggesting its possible use as a therapeutic agent in breast cancer.

Original languageEnglish (US)
Pages (from-to)1276-1286
Number of pages11
JournalCellular Signalling
Volume24
Issue number6
DOIs
StatePublished - Jun 1 2012

Fingerprint

src-Family Kinases
Aurora Kinase B
Breast Neoplasms
Phosphorylation
Cell Proliferation
Paxillin
Caveolin 1
Polyploidy
Cytokinesis
Transcriptome
Histones
Genes
Cluster Analysis
SU 6656
Cell Cycle
Fibroblasts
Neoplasm Metastasis
Survival
Dasatinib
Neoplasms

Keywords

  • Aurora B kinase
  • Dasatinib
  • MDA-MB-231
  • PP2
  • SFKs
  • SU6656

ASJC Scopus subject areas

  • Cell Biology

Cite this

Sánchez-Bailón, M. P., Calcabrini, A., Gómez-Domínguez, D., Morte, B., Martín-Forero, E., Gómez-López, G., ... Martín-Pérez, J. (2012). Src kinases catalytic activity regulates proliferation, migration and invasiveness of MDA-MB-231 breast cancer cells. Cellular Signalling, 24(6), 1276-1286. https://doi.org/10.1016/j.cellsig.2012.02.011

Src kinases catalytic activity regulates proliferation, migration and invasiveness of MDA-MB-231 breast cancer cells. / Sánchez-Bailón, María Pilar; Calcabrini, Annarica; Gómez-Domínguez, Daniel; Morte, Beatriz; Martín-Forero, Esther; Gómez-López, Gonzalo; Molinari, Agnese; Wagner, Kay Uwe; Martín-Pérez, Jorge.

In: Cellular Signalling, Vol. 24, No. 6, 01.06.2012, p. 1276-1286.

Research output: Contribution to journalArticle

Sánchez-Bailón, MP, Calcabrini, A, Gómez-Domínguez, D, Morte, B, Martín-Forero, E, Gómez-López, G, Molinari, A, Wagner, KU & Martín-Pérez, J 2012, 'Src kinases catalytic activity regulates proliferation, migration and invasiveness of MDA-MB-231 breast cancer cells', Cellular Signalling, vol. 24, no. 6, pp. 1276-1286. https://doi.org/10.1016/j.cellsig.2012.02.011
Sánchez-Bailón MP, Calcabrini A, Gómez-Domínguez D, Morte B, Martín-Forero E, Gómez-López G et al. Src kinases catalytic activity regulates proliferation, migration and invasiveness of MDA-MB-231 breast cancer cells. Cellular Signalling. 2012 Jun 1;24(6):1276-1286. https://doi.org/10.1016/j.cellsig.2012.02.011
Sánchez-Bailón, María Pilar ; Calcabrini, Annarica ; Gómez-Domínguez, Daniel ; Morte, Beatriz ; Martín-Forero, Esther ; Gómez-López, Gonzalo ; Molinari, Agnese ; Wagner, Kay Uwe ; Martín-Pérez, Jorge. / Src kinases catalytic activity regulates proliferation, migration and invasiveness of MDA-MB-231 breast cancer cells. In: Cellular Signalling. 2012 ; Vol. 24, No. 6. pp. 1276-1286.
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