TY - JOUR
T1 - Lysophosphatidic acid and sphingosine-1-phosphate promote morphogenesis and block invasion of prostate cancer cells in three-dimensional organotypic models
AU - Härmä, Ville
AU - Knuuttila, M.
AU - Virtanen, Johannes
AU - Mirtti, T.
AU - Kohonen, P.
AU - Kovanen, P.
AU - Happonen, A.
AU - Kaewphan, S.
AU - Ahonen, I.
AU - Kallioniemi, O.
AU - Grafström, Roland
AU - Lötjönen, Jyrki
AU - Nees, Matthias
PY - 2012
Y1 - 2012
N2 - Normal prostate and some malignant prostate cancer (PrCa) cell lines
undergo acinar differentiation and form spheroids in three-dimensional
(3-D) organotypic culture. Acini formed by PC-3 and PC-3M, less
pronounced also in other PrCa cell lines, spontaneously undergo an
invasive switch, leading to the disintegration of epithelial structures
and the basal lamina, and formation of invadopodia. This demonstrates
the highly dynamic nature of epithelial plasticity, balancing
epithelial-to-mesenchymal transition against metastable acinar
differentiation. This study assessed the role of lipid metabolites on
epithelial maturation. PC-3 cells completely failed to form acinar
structures in delipidated serum. Adding back lysophosphatidic acid (LPA)
and sphingosine-1-phosphate (S1P) rescued acinar morphogenesis and
repressed invasion effectively. Blocking LPA receptor 1 (LPAR1)
functions by siRNA (small interference RNA) or the specific LPAR1
inhibitor Ki16425 promoted invasion, while silencing of other
G-protein-coupled receptors responsive to LPA or S1P mainly caused
growth arrest or had no effects. The G-proteins Gα12/13 and Gαi
were identified as key mediators of LPA signalling via stimulation of
RhoA and Rho kinases ROCK1 and 2, activating Rac1, while inhibition of
adenylate cyclase and accumulation of cAMP may be secondary. Interfering
with these pathways specifically impeded epithelial polarization in
transformed cells. In contrast, blocking the same pathways in
non-transformed, normal cells promoted differentiation. We conclude that
LPA and LPAR1 effectively promote epithelial maturation and block
invasion of PrCa cells in 3-D culture. The analysis of clinical
transcriptome data confirmed reduced expression of LPAR1 in a subset of
PrCa's. Our study demonstrates a metastasis-suppressor function for
LPAR1 and Gα12/13 signalling, regulating cell motility and invasion versus epithelial maturation.
AB - Normal prostate and some malignant prostate cancer (PrCa) cell lines
undergo acinar differentiation and form spheroids in three-dimensional
(3-D) organotypic culture. Acini formed by PC-3 and PC-3M, less
pronounced also in other PrCa cell lines, spontaneously undergo an
invasive switch, leading to the disintegration of epithelial structures
and the basal lamina, and formation of invadopodia. This demonstrates
the highly dynamic nature of epithelial plasticity, balancing
epithelial-to-mesenchymal transition against metastable acinar
differentiation. This study assessed the role of lipid metabolites on
epithelial maturation. PC-3 cells completely failed to form acinar
structures in delipidated serum. Adding back lysophosphatidic acid (LPA)
and sphingosine-1-phosphate (S1P) rescued acinar morphogenesis and
repressed invasion effectively. Blocking LPA receptor 1 (LPAR1)
functions by siRNA (small interference RNA) or the specific LPAR1
inhibitor Ki16425 promoted invasion, while silencing of other
G-protein-coupled receptors responsive to LPA or S1P mainly caused
growth arrest or had no effects. The G-proteins Gα12/13 and Gαi
were identified as key mediators of LPA signalling via stimulation of
RhoA and Rho kinases ROCK1 and 2, activating Rac1, while inhibition of
adenylate cyclase and accumulation of cAMP may be secondary. Interfering
with these pathways specifically impeded epithelial polarization in
transformed cells. In contrast, blocking the same pathways in
non-transformed, normal cells promoted differentiation. We conclude that
LPA and LPAR1 effectively promote epithelial maturation and block
invasion of PrCa cells in 3-D culture. The analysis of clinical
transcriptome data confirmed reduced expression of LPAR1 in a subset of
PrCa's. Our study demonstrates a metastasis-suppressor function for
LPAR1 and Gα12/13 signalling, regulating cell motility and invasion versus epithelial maturation.
KW - prostate cancer
KW - epithelial plasticity
KW - bioactive lipids
KW - G-protein coupled receptors
KW - lysophosphatidic acid
KW - sphingosine-1-phosphate
U2 - 10.1038/onc.2011.396
DO - 10.1038/onc.2011.396
M3 - Article
SN - 0950-9232
VL - 31
SP - 2075
EP - 2089
JO - Oncogene
JF - Oncogene
IS - 16
ER -
