Abstract
Cell migration is a fundamental feature of tumour metastasis and angiogenesis. It is regulated by a variety of signalling molecules including H2O2 and Ca(2+) Here, we asked whether the H2O2-sensitive transient receptor potential melastatin 2 (TRPM2) Ca(2+) channel serves as a molecular link between H2O2 and Ca(2+) H2O2-mediated activation of TRPM2 channels induced filopodia formation, loss of actin stress fibres and disassembly of focal adhesions, leading to increased migration of HeLa and prostate cancer (PC)-3 cells. Activation of TRPM2 channels, however, caused intracellular release of not only Ca(2+) but also of Zn(2+) Intriguingly, elevation of intracellular Zn(2+) faithfully reproduced all of the effects of H2O2, whereas Ca(2+) showed opposite effects. Interestingly, H2O2 caused increased trafficking of Zn(2+)-enriched lysosomes to the leading edge of migrating cells, presumably to impart polarisation of Zn(2+) location. Thus, our results indicate that a reciprocal interplay between Ca(2+) and Zn(2+) regulates actin remodelling and cell migration; they call for a revision of the current notion that implicates an exclusive role for Ca(2+) in cell migration.
Highlights
Cell migration is a fundamental feature of angiogenesis (Lamalice et al, 2007), the leukocyte immune response (Klyubin et al, 1996) and tumour cell invasion (Ridley et al, 2003)
We found that transient receptor potential melastatin 2 (TRPM2) activation increases the cytosolic levels of Ca2+, and Zn2+, and that Ca2+ and Zn2+ regulate actin cytoskeleton dynamics, focal adhesion dynamics and cell migration in a reciprocal manner, with Zn2+ playing a dominant role
H2O2-induced actin remodelling in cancer cells is dependent on TRPM2 channels Given that H2O2 is cytotoxic and its toxicity can vary depending on the cell type (Manna et al, 2015), we first screened prostate cancer (PC)-3 and HeLa cells for their sensitivity to H2O2 and chose a concentration (
Summary
Cell migration is a fundamental feature of angiogenesis (Lamalice et al, 2007), the leukocyte immune response (Klyubin et al, 1996) and tumour cell invasion (Ridley et al, 2003). Changes in cell morphology are driven by the constant remodelling of the actin cytoskeleton into structures that coordinate cell migration (Gardel et al, 2010; Mattila and Lappalainen, 2008; Ridley et al, 2003; Small et al, 2002; Tojkander et al, 2012) These include filopodia (Mattila and Lappalainen, 2008), lamellipodia (Small et al, 2002) and stress fibres (Nobes and Hall, 1995; Tojkander et al, 2012).
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