El pdf del artículo es la versión post-print.-- et al.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
p27Kip1 expression and reduced c-Myc levels, restraining G1-S transition. In contrast,
SU6656 did not modify p27Kip1 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.This work was supported by grants from Ministerio de Ciencia e Innovación [SAF2009-09254] and Fundación de Investigación Médica Mutua Madrileña. M.P. S-B. was supported by a FPI fellowship from Ministerio de Ciencia e Innovación, and A.C. was partially supported by a grant from Fundación de Investigación Médica Mutua Madrileña.Peer reviewe
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