Journal
ONCOGENE
Volume 30, Issue 18, Pages 2108-2122Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2010.593
Keywords
P2X(7) receptors; migration; SK3 channels; cancer cell invasion; cystein cathepsins
Funding
- Biotechnology and Biological Sciences Research Council
- Ligue Nationale Contre le Cancer Region Centre
- Association CANCEN
- Ministere de la Recherche et des Technologies
- 'Institut National de la Sante et de la Recherche Medicale' (INSERM)
- 'Partenariat Hubert Curien-Alliance' from the French Foreign and European Ministry
- French Embassy in the United Kingdom
- Institut National du Cancer (INCa)
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ATP-gated P2X(7) receptors (P2X(7)R) are unusual plasma membrane ion channels that have been extensively studied in immune cells. More recently, P2X(7)R have been described as potential cancer cell biomarkers. However, mechanistic links between P2X(7)R and cancer cell processes are unknown. Here, we show, in the highly aggressive human breast cancer cell line MDA-MB-435s, that P2X(7) receptor is highly expressed and fully functional. Its activation is responsible for the extension of neurite-like cellular prolongations, of the increase in cell migration by 35% and in cell invasion through extracellular matrix by 150%. The change in cancer cell morphology and the increased migration appeared to be due to the activation of Ca2+-activated SK3 potassium channels. The enhanced invasion through the extracellular matrix was related to the increase of mature forms of cysteine cathepsins in the extracellular medium, which was independent of SK3 channel activity and not associated with cell death. Pharmacological targeting of P2X(7)R in vivo was crucial for cell invasiveness in a zebrafish model of metastases. Our results demonstrate a novel mechanistic link between P2X(7)R functionality in cancer cells and invasiveness, a key parameter in tumour growth and in the development of metastases. They also suggest a potential therapeutic role for the newly developed P2X(7)R antagonists. Oncogene (2011) 30, 2108-2122; doi:10.1038/onc.2010.593; published online 17 January 2011
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