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Title: Anandamide inhibits adhesion and migration of breast cancer cells

Abstract

The endocannabinoid system regulates cell proliferation in human breast cancer cells. We reasoned that stimulation of cannabinoid CB{sub 1} receptors could induce a non-invasive phenotype in breast mtastatic cells. In a model of metastatic spreading in vivo, the metabolically stable anandamide analogue, 2-methyl-2'-F-anandamide (Met-F-AEA), significantly reduced the number and dimension of metastatic nodes, this effect being antagonized by the selective CB{sub 1} antagonist SR141716A. In MDA-MB-231 cells, a highly invasive human breast cancer cell line, and in TSA-E1 cells, a murine breast cancer cell line, Met-F-AEA inhibited adhesion and migration on type IV collagen in vitro without modifying integrin expression: both these effects were antagonized by SR141716A. In order to understand the molecular mechanism involved in these processes, we analyzed the phosphorylation of FAK and Src, two tyrosine kinases involved in migration and adhesion. In Met-F-AEA-treated cells, we observed a decreased tyrosine phosphorylation of both FAK and Src, this effect being attenuated by SR141716A. We propose that CB{sub 1} receptor agonists inhibit tumor cell invasion and metastasis by modulating FAK phosphorylation, and that CB{sub 1} receptor activation might represent a novel therapeutic strategy to slow down the growth of breast carcinoma and to inhibit its metastatic diffusion in vivo.

Authors:
 [1];  [1];  [2];  [1];  [1];  [3];  [4];  [4];  [1];  [5];  [2];  [6];  [7]
  1. Dipartimento di Scienze Farmaceutiche, Endocannabinoid Research Group, Universita degli Studi di Salerno, Fisciano (Italy)
  2. Istituto di Endocrinologia e Oncologia Sperimentale del CNR e Dipartimento di Biologia e Patologia Cellulare e Molecolare, Universita di Napoli Federico II (Italy)
  3. Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica, Universita di Napoli Federico II (Italy)
  4. Laboratorio di Biochimica, IRCCS 'S. de Bellis', Castellana Grotte (Bari) (Italy)
  5. (Italy)
  6. Istituto di Chimica Biomolecolare, C.N.R., Pozzuoli (Namibia) (Italy). E-mail: vdimarzo@icmib.na.cnr.it
  7. Dipartimento di Scienze Farmaceutiche, Endocannabinoid Research Group, Universita degli Studi di Salerno, Fisciano (Sa) (Italy). E-mail: maubiful@unina.it
Publication Date:
OSTI Identifier:
20775337
Resource Type:
Journal Article
Resource Relation:
Journal Name: Experimental Cell Research; Journal Volume: 312; Journal Issue: 4; Other Information: DOI: 10.1016/j.yexcr.2005.10.024; PII: S0014-4827(05)00509-4; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CARCINOMAS; CELL PROLIFERATION; COLLAGEN; IN VITRO; IN VIVO; MAMMARY GLANDS; METASTASES; PHENOTYPE; PHOSPHORYLATION; PHOSPHOTRANSFERASES; RECEPTORS; TUMOR CELLS; TYROSINE

Citation Formats

Grimaldi, Claudia, Pisanti, Simona, Laezza, Chiara, Malfitano, Anna Maria, Santoro, Antonietta, Vitale, Mario, Caruso, Maria Gabriella, Notarnicola, Maria, Iacuzzo, Irma, Istituto di Endocrinologia e Oncologia Sperimentale del CNR e Dipartimento di Biologia e Patologia Cellulare e Molecolare, Universita di Napoli Federico II, Portella, Giuseppe, Di Marzo, Vincenzo, and Bifulco, Maurizio. Anandamide inhibits adhesion and migration of breast cancer cells. United States: N. p., 2006. Web. doi:10.1016/j.yexcr.2005.10.024.
Grimaldi, Claudia, Pisanti, Simona, Laezza, Chiara, Malfitano, Anna Maria, Santoro, Antonietta, Vitale, Mario, Caruso, Maria Gabriella, Notarnicola, Maria, Iacuzzo, Irma, Istituto di Endocrinologia e Oncologia Sperimentale del CNR e Dipartimento di Biologia e Patologia Cellulare e Molecolare, Universita di Napoli Federico II, Portella, Giuseppe, Di Marzo, Vincenzo, & Bifulco, Maurizio. Anandamide inhibits adhesion and migration of breast cancer cells. United States. doi:10.1016/j.yexcr.2005.10.024.
Grimaldi, Claudia, Pisanti, Simona, Laezza, Chiara, Malfitano, Anna Maria, Santoro, Antonietta, Vitale, Mario, Caruso, Maria Gabriella, Notarnicola, Maria, Iacuzzo, Irma, Istituto di Endocrinologia e Oncologia Sperimentale del CNR e Dipartimento di Biologia e Patologia Cellulare e Molecolare, Universita di Napoli Federico II, Portella, Giuseppe, Di Marzo, Vincenzo, and Bifulco, Maurizio. Wed . "Anandamide inhibits adhesion and migration of breast cancer cells". United States. doi:10.1016/j.yexcr.2005.10.024.
@article{osti_20775337,
title = {Anandamide inhibits adhesion and migration of breast cancer cells},
author = {Grimaldi, Claudia and Pisanti, Simona and Laezza, Chiara and Malfitano, Anna Maria and Santoro, Antonietta and Vitale, Mario and Caruso, Maria Gabriella and Notarnicola, Maria and Iacuzzo, Irma and Istituto di Endocrinologia e Oncologia Sperimentale del CNR e Dipartimento di Biologia e Patologia Cellulare e Molecolare, Universita di Napoli Federico II and Portella, Giuseppe and Di Marzo, Vincenzo and Bifulco, Maurizio},
abstractNote = {The endocannabinoid system regulates cell proliferation in human breast cancer cells. We reasoned that stimulation of cannabinoid CB{sub 1} receptors could induce a non-invasive phenotype in breast mtastatic cells. In a model of metastatic spreading in vivo, the metabolically stable anandamide analogue, 2-methyl-2'-F-anandamide (Met-F-AEA), significantly reduced the number and dimension of metastatic nodes, this effect being antagonized by the selective CB{sub 1} antagonist SR141716A. In MDA-MB-231 cells, a highly invasive human breast cancer cell line, and in TSA-E1 cells, a murine breast cancer cell line, Met-F-AEA inhibited adhesion and migration on type IV collagen in vitro without modifying integrin expression: both these effects were antagonized by SR141716A. In order to understand the molecular mechanism involved in these processes, we analyzed the phosphorylation of FAK and Src, two tyrosine kinases involved in migration and adhesion. In Met-F-AEA-treated cells, we observed a decreased tyrosine phosphorylation of both FAK and Src, this effect being attenuated by SR141716A. We propose that CB{sub 1} receptor agonists inhibit tumor cell invasion and metastasis by modulating FAK phosphorylation, and that CB{sub 1} receptor activation might represent a novel therapeutic strategy to slow down the growth of breast carcinoma and to inhibit its metastatic diffusion in vivo.},
doi = {10.1016/j.yexcr.2005.10.024},
journal = {Experimental Cell Research},
number = 4,
volume = 312,
place = {United States},
year = {Wed Feb 15 00:00:00 EST 2006},
month = {Wed Feb 15 00:00:00 EST 2006}
}
  • LIM and SH3 protein (LASP-1), initially identified from human breast cancer, is a specific focal adhesion protein involved in cell migration. LASP-1 is an actin binding protein, which also interacts with the proline-rich domains of zyxin, a scaffolding protein required for cell movement and gene transcription. In the present work, we analyzed the effect of LASP-1 on different human breast cancer cell lines. Transfection with LASP-1-specific siRNA resulted in a reduced protein level of LASP-1 in BT-20 and MCF-7 cell lines. The siRNA-treated cells were arrested in G2/M phase of cell cycle, and proliferation of the tumor cells was suppressedmore » by 30-50% corresponding to around 50% of the cells being transfected successfully as seen by immunofluorescence. In addition, tumor cells showed a 50% reduced migration after siRNA treatment, while overexpression of LASP-1 in non-tumor PTK-2 cells, which do not express endogenous LASP-1, resulted in a significant increase in cell motility. LASP-1 silencing is accompanied with a reduced binding of the of LASP-1 binding partner zyxin to focal contacts without changes in actin stress fiber organization as observed in immunofluorescence experiments. The data provide evidence for an essential role of LASP-1 in tumor cell growth and migration, possibly by influencing the localization of zyxin.« less
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