Lysophosphatidic Acid and Sphingosine-1-phosphate Promote Morphogenesis and Block Invasion of Prostate Cancer Cells in Three-dimensional Organotypic Models

Overview

Journal Oncogene

Specialties Molecular Biology
Oncology

Date 2011 Oct 15

PMID 21996742

Citations 30

Authors

V Harma

M Knuuttila

J Virtanen

T Mirtti

P Kohonen

P Kovanen

A Happonen

S Kaewphan

I Ahonen

O Kallioniemi

R Grafstrom

J Lotjonen

M Nees

Affiliations

Soon will be listed here.

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 Gα(12/13) and Gα(i) 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 Gα(12/13) signalling, regulating cell motility and invasion versus epithelial maturation.

Citing Articles

Downregulation of LPAR1 Promotes Invasive Behavior in Papillary Thyroid Carcinoma Cells.

Hosseini Z, Rajabi F, Morovatshoar R, Ashrafpour M, Behboodi P, Zareie D Cancer Inform. 2024; 23:11769351241277012.

PMID: 39253536 PMC: 11382228. DOI: 10.1177/11769351241277012.

Lipid metabolism and its implications in tumor cell plasticity and drug resistance: what we learned thus far?.

Vishwa R, BharathwajChetty B, Girisa S, Aswani B, AlQahtani M, Abbas M Cancer Metastasis Rev. 2024; 43(1):293-319.

PMID: 38438800 DOI: 10.1007/s10555-024-10170-1.

Optimization of a Three-Dimensional Culturing Method for Assessing the Impact of Cisplatin on Notch Signaling in Head and Neck Squamous Cell Carcinoma (HNSCC).

Anameric A, Czerwonka A, Nees M Cancers (Basel). 2023; 15(22).

PMID: 38001580 PMC: 10670464. DOI: 10.3390/cancers15225320.

LPAR1 and aberrantly expressed LPAR3 differentially promote the migration and proliferation of malignant peripheral nerve sheath tumor cells.

Doutt S, Fromm Longo J, Carroll S Glia. 2022; 71(3):742-757.

PMID: 36416236 PMC: 9868101. DOI: 10.1002/glia.24308.

Reduction of LPAR1 Expression in Neuroblastoma Promotes Tumor Cell Migration.

Liu X, Pei M, Yu Y, Wang X, Gui J Cancers (Basel). 2022; 14(14).

PMID: 35884407 PMC: 9322936. DOI: 10.3390/cancers14143346.

References

Sekine Y, Suzuki K, Remaley A . HDL and sphingosine-1-phosphate activate stat3 in prostate cancer DU145 cells via ERK1/2 and S1P receptors, and promote cell migration and invasion. Prostate. 2010; 71(7):690-9. PMC: 4159087. DOI: 10.1002/pros.21285. View

Wang F, Ariztia E, Boyd L, Horton F, Smicun Y, Hetherington J . Lysophosphatidic acid (LPA) effects on endometrial carcinoma in vitro proliferation, invasion, and matrix metalloproteinase activity. Gynecol Oncol. 2010; 117(1):88-95. DOI: 10.1016/j.ygyno.2009.12.012. View

Vogler R, Sauer B, Kim D, Schafer-Korting M, Kleuser B . Sphingosine-1-phosphate and its potentially paradoxical effects on critical parameters of cutaneous wound healing. J Invest Dermatol. 2003; 120(4):693-700. DOI: 10.1046/j.1523-1747.2003.12096.x. View

Lee M, Thangada S, Liu C, THOMPSON B, Hla T . Lysophosphatidic acid stimulates the G-protein-coupled receptor EDG-1 as a low affinity agonist. J Biol Chem. 1998; 273(34):22105-12. DOI: 10.1074/jbc.273.34.22105. View

Li H, Wang D, Zhang H, Kirmani K, Zhao Z, Steinmetz R . Lysophosphatidic acid stimulates cell migration, invasion, and colony formation as well as tumorigenesis/metastasis of mouse ovarian cancer in immunocompetent mice. Mol Cancer Ther. 2009; 8(6):1692-701. DOI: 10.1158/1535-7163.MCT-08-1106. View

Zhang C, Baker D, Yasuda S, Makarova N, Balazs L, Johnson L . Lysophosphatidic acid induces neointima formation through PPARgamma activation. J Exp Med. 2004; 199(6):763-74. PMC: 2212723. DOI: 10.1084/jem.20031619. View

Olivera A, Spiegel S . Sphingosine-1-phosphate as second messenger in cell proliferation induced by PDGF and FCS mitogens. Nature. 1993; 365(6446):557-60. DOI: 10.1038/365557a0. View

Gobeil Jr F, Bernier S, Vazquez-Tello A, Brault S, Beauchamp M, Quiniou C . Modulation of pro-inflammatory gene expression by nuclear lysophosphatidic acid receptor type-1. J Biol Chem. 2003; 278(40):38875-83. DOI: 10.1074/jbc.M212481200. View

Mani S, Guo W, Liao M, Eaton E, Ayyanan A, Zhou A . The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008; 133(4):704-15. PMC: 2728032. DOI: 10.1016/j.cell.2008.03.027. View

10.

Guo R, Kasbohm E, Arora P, Sample C, Baban B, Sud N . Expression and function of lysophosphatidic acid LPA1 receptor in prostate cancer cells. Endocrinology. 2006; 147(10):4883-92. DOI: 10.1210/en.2005-1635. View

11.

Akbar H, Cancelas J, Williams D, Zheng J, Zheng Y . Rational design and applications of a Rac GTPase-specific small molecule inhibitor. Methods Enzymol. 2006; 406:554-65. DOI: 10.1016/S0076-6879(06)06043-5. View

12.

Harper K, Arsenault D, Boulay-Jean S, Lauzier A, Lucien F, Dubois C . Autotaxin promotes cancer invasion via the lysophosphatidic acid receptor 4: participation of the cyclic AMP/EPAC/Rac1 signaling pathway in invadopodia formation. Cancer Res. 2010; 70(11):4634-43. DOI: 10.1158/0008-5472.CAN-09-3813. View

13.

Hasegawa Y, Murph M, Yu S, Tigyi G, Mills G . Lysophosphatidic acid (LPA)-induced vasodilator-stimulated phosphoprotein mediates lamellipodia formation to initiate motility in PC-3 prostate cancer cells. Mol Oncol. 2008; 2(1):54-69. PMC: 2597858. DOI: 10.1016/j.molonc.2008.03.009. View

14.

Westermann A, Havik E, Postma F, Beijnen J, Dalesio O, Moolenaar W . Malignant effusions contain lysophosphatidic acid (LPA)-like activity. Ann Oncol. 1998; 9(4):437-42. DOI: 10.1023/a:1008217129273. View

15.

Shutes A, Onesto C, Picard V, Leblond B, Schweighoffer F, Der C . Specificity and mechanism of action of EHT 1864, a novel small molecule inhibitor of Rac family small GTPases. J Biol Chem. 2007; 282(49):35666-78. DOI: 10.1074/jbc.M703571200. View

16.

Hao F, Tan M, Xu X, Han J, Miller D, Tigyi G . Lysophosphatidic acid induces prostate cancer PC3 cell migration via activation of LPA(1), p42 and p38alpha. Biochim Biophys Acta. 2007; 1771(7):883-92. PMC: 3446792. DOI: 10.1016/j.bbalip.2007.04.010. View

17.

Evelyn C, Bell J, Ryu J, Wade S, Kocab A, Harzdorf N . Design, synthesis and prostate cancer cell-based studies of analogs of the Rho/MKL1 transcriptional pathway inhibitor, CCG-1423. Bioorg Med Chem Lett. 2009; 20(2):665-72. PMC: 2818594. DOI: 10.1016/j.bmcl.2009.11.056. View

18.

Kalluri R, Weinberg R . The basics of epithelial-mesenchymal transition. J Clin Invest. 2009; 119(6):1420-8. PMC: 2689101. DOI: 10.1172/JCI39104. View

19.

Snider A, Gandy K, Obeid L . Sphingosine kinase: Role in regulation of bioactive sphingolipid mediators in inflammation. Biochimie. 2010; 92(6):707-15. PMC: 2878898. DOI: 10.1016/j.biochi.2010.02.008. View

20.

Chu J, Yu S, Hayward S, Chan F . Development of a three-dimensional culture model of prostatic epithelial cells and its use for the study of epithelial-mesenchymal transition and inhibition of PI3K pathway in prostate cancer. Prostate. 2008; 69(4):428-42. DOI: 10.1002/pros.20897. View