Inhibition of stathmin1 accelerates the metastatic process.
The oncoprotein stathmin 1 (STMN1) is upregulated in most, if not all, cancers of epithelial cell origin; therefore STMN1 is considered a target for cancer therapy. However, its role during metastasis has not been investigated. Here, we report for the first time that STMN1 strongly inhibits metastatic behavior in both normal epithelial and cancerous epithelial cells. Initially, loss-of-STMN1 compromises cell-cell adhesion. This is followed by epithelial-to-mesenchymal transition (EMT), increased cell migration, and metastasis via cooperative activation of p38 and through TGF-β-independent and -dependent mechanisms. In contrast, expressing STMN1 restores cell-cell adhesion and reverses the metastatic cascade. Primary prostate epithelial cell cultures from benign to undifferentiated adenocarcinoma (UA) clinical biopsies show that EMT-like cells arise while the cancer is still organ-confined and that their emergence is tumor-stage specific. Furthermore, primary EMT-like cells exhibit metastatic behavior both in vitro and in vivo as compared with their non-EMT counterpart. These observations predict that using STMN1 as a generic therapeutic target might accelerate metastasis. Instead, there may be a tumor stage-specific window-of-opportunity in which conserving STMN1 expression is required to inhibit emergence of metastatic disease.
Department of Environmental Health, University of Cincinnati, Cincinnati, OH, USA.
Karin
K
Williams
Ritwik
R
Ghosh
Premkumar Vummidi
PV
Giridhar
Guangyu
G
Gu
Thomas
T
Case
Scott M
SM
Belcher
Susan
S
Kasper
D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers; D015536:Down-Regulation; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis; D015398:Signal Transduction; D050777:Stathmin / Q000037:antagonists & inhibitors*
D017931:DNA Primers; C493995:STMN1 protein, human; D050777:Stathmin