Lysophosphatidic acid and sphingosine-1-phosphate promote morphogenesis and block invasion of prostate cancer cells in three-dimensional organotypic models

Ville Härmä, M. Knuuttila, Johannes Virtanen, T. Mirtti, P. Kohonen, P. Kovanen, A. Happonen, S. Kaewphan, I. Ahonen, O. Kallioniemi, Roland Grafström, Jyrki Lötjönen, Matthias Nees (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

23 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)2075-2089
JournalOncogene
Volume31
Issue number16
DOIs
Publication statusPublished - 2012
MoE publication typeA1 Journal article-refereed

Fingerprint

Lysophosphatidic Acid Receptors
Morphogenesis
Prostatic Neoplasms
G12-G13 GTP-Binding Protein alpha Subunits
Cell Line
rho-Associated Kinases
Epithelial-Mesenchymal Transition
Gene Expression Profiling
G-Protein-Coupled Receptors
RNA Interference
Adenylyl Cyclases
Basement Membrane
Cell Movement
lysophosphatidic acid
sphingosine 1-phosphate
Prostate
Cell Differentiation
Neoplasm Metastasis
Lipids
Growth

Keywords

  • prostate cancer
  • epithelial plasticity
  • bioactive lipids
  • G-protein coupled receptors
  • lysophosphatidic acid
  • sphingosine-1-phosphate

Cite this

Härmä, Ville ; Knuuttila, M. ; Virtanen, Johannes ; Mirtti, T. ; Kohonen, P. ; Kovanen, P. ; Happonen, A. ; Kaewphan, S. ; Ahonen, I. ; Kallioniemi, O. ; Grafström, Roland ; Lötjönen, Jyrki ; Nees, Matthias. / Lysophosphatidic acid and sphingosine-1-phosphate promote morphogenesis and block invasion of prostate cancer cells in three-dimensional organotypic models. In: Oncogene. 2012 ; Vol. 31, No. 16. pp. 2075-2089.
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abstract = "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.",
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Härmä, V, Knuuttila, M, Virtanen, J, Mirtti, T, Kohonen, P, Kovanen, P, Happonen, A, Kaewphan, S, Ahonen, I, Kallioniemi, O, Grafström, R, Lötjönen, J & Nees, M 2012, 'Lysophosphatidic acid and sphingosine-1-phosphate promote morphogenesis and block invasion of prostate cancer cells in three-dimensional organotypic models', Oncogene, vol. 31, no. 16, pp. 2075-2089. https://doi.org/10.1038/onc.2011.396

Lysophosphatidic acid and sphingosine-1-phosphate promote morphogenesis and block invasion of prostate cancer cells in three-dimensional organotypic models. / Härmä, Ville; Knuuttila, M.; Virtanen, Johannes; Mirtti, T.; Kohonen, P.; Kovanen, P.; Happonen, A.; Kaewphan, S.; Ahonen, I.; Kallioniemi, O.; Grafström, Roland; Lötjönen, Jyrki; Nees, Matthias (Corresponding Author).

In: Oncogene, Vol. 31, No. 16, 2012, p. 2075-2089.

Research output: Contribution to journalArticleScientificpeer-review

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

VL - 31

SP - 2075

EP - 2089

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 16

ER -