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

Meng-Ru Shen *†, Cheng-Yang Chou †, Joseph A. Browning *, Robert J. Wilkins * and J. Clive Ellory *

1. This study was aimed at identifying the signalling pathways involved in the activation of volume-regulatory mechanisms of human cervical cancer cells.
2. Osmotic swelling of human cervical cancer cells induced a substantial increase in intracellular Ca²⁺ ([Ca²⁺]_i) by the activation of Ca²⁺ entry across the cell membrane, as well as Ca²⁺ release from intracellular stores. This Ca²⁺ signalling was critical for the normal regulatory volume decrease (RVD) response.
3. 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 Na₃VO_4. However, the Src family of tyrosine kinases was not involved in regulation of the swelling-activated Cl^- channel.
4. 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.
5. 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 Ca²⁺ entry and depended on tyrosine kinase and mitogen-activated/ERK-activating kinase (MEK) activity.
6. Considering the results overall, osmotic swelling promotes the activation of tyrosine kinase and ERK1/ERK2 and raises intracellular Ca²⁺, all of which play a crucial role in the volume-regulatory mechanism of human cervical cancer cells.

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