Human cervical cancer cells use Ca2+ signalling, protein tyrosine phosphorylation and MAP kinase in regulatory volume decrease

• Published in: The Journal of physiology 2001-12, Vol.537 (2), p.347-362
• Main Authors: Shen, Meng‐Ru, Chou, Cheng‐Yang, Browning, Joseph A., Wilkins, Robert J., Ellory, J. Clive
• Format: Article
• Language: English
• Subjects: Calcium Signaling; Enzyme Activation; Female; Humans; Hypotonic Solutions - pharmacology; Mitogen-Activated Protein Kinases - metabolism; Mitogen-Activated Protein Kinases - physiology; Original; Osmosis; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Shock - metabolism; Tumor Cells, Cultured; Tyrosine - metabolism; Uterine Cervical Neoplasms - metabolism; Uterine Cervical Neoplasms - pathology
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1111/j.1469-7793.2001.00347.x

This study was aimed at identifying the signalling pathways involved in the activation of volume-regulatory mechanisms of human cervical cancer cells. Osmotic swelling of human cervical cancer cells induced a substantial increase in intracellular Ca 2+ ([Ca 2+ ] i ) by the activation of Ca 2+ entry across the cell membrane, as well as Ca 2+ release from intracellular stores. This Ca 2+ signalling was critical for the normal regulatory volume decrease (RVD) response. The activation of swelling-activated ion and taurine transport was significantly inhibited by tyrosine kinase inhibitors (genistein and tyrphostin AG 1478) and potentiated by the tyrosine phosphatase inhibitor Na 3 VO 4. However, the Src family of tyrosine kinases was not involved in regulation of the swelling-activated Cl − channel. Cell swelling triggered mitogen-activated protein (MAP) kinase cascades leading to the activation of extracellular signal-regulated kinase 1 and 2 (ERK1/ERK2) and p38 kinase. The volume-responsive ERK1/ERK2 signalling pathway linked with the activation of K + and Cl − channels, and taurine transport. However, the volume-regulatory mechanism was independent of the activation of p38 MAP kinase. The phosphorylated ERK1/ERK2 expression following a hypotonic shock was up-regulated by protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) and down-regulated by PKC inhibitor staurosporine. The response of ERK activation to hypotonicity also required Ca 2+ entry and depended on tyrosine kinase and mitogen-activated/ERK-activating kinase (MEK) activity. Considering the results overall, osmotic swelling promotes the activation of tyrosine kinase and ERK1/ERK2 and raises intracellular Ca 2+ , all of which play a crucial role in the volume-regulatory mechanism of human cervical cancer cells.