Dataset Information

Calcium wave signaling in cancer cells.

ABSTRACT: Ca(2+) functions as an important signaling messenger right from beginning of life to the final moments of the end of life. Ca(2+) is needed at several steps of the cell cycle such as early G(1), at the G(1)/S, and G(2)/M transitions. The Ca(2+) signals in the form of time-dependent changes in intracellular Ca(2+) concentrations, [Ca(2+)](i), are presented as brief spikes organized into regenerative Ca(2+) waves. Ca(2+)-mediated signaling pathways have also been shown to play important roles in carcinogenesis such as transformation of normal cells to cancerous cells, tumor formation and growth, invasion, angiogenesis and metastasis. Since the global Ca(2+) oscillations arise from Ca(2+) waves initiated locally, it results in stochastic oscillations because although each cell has many IP(3)Rs and Ca(2+) ions, the law of large numbers does not apply to the initiating event which is restricted to very few IP(3)Rs due to steep Ca(2+) concentration gradients. The specific Ca(2+) signaling information is likely to be encoded in a calcium code as the amplitude, duration, frequency, waveform or timing of Ca(2+) oscillations and decoded again at a later stage. Since Ca(2+) channels or pumps involved in regulating Ca(2+) signaling pathways show altered expression in cancer, one can target these Ca(2+) channels and pumps as therapeutic options to decrease proliferation of cancer cells and to promote their apoptosis. These studies can provide novel insights into alterations in Ca(2+) wave patterns in carcinogenesis and lead to the development of newer technologies based on Ca(2+) waves for the diagnosis and therapy of cancer.

SUBMITTER: Parkash J

PROVIDER: S-EPMC2974775 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Calcium wave signaling in cancer cells.

Parkash Jai J Asotra Kamlesh K

Life sciences 20100925 19-22

Ca(2+) functions as an important signaling messenger right from beginning of life to the final moments of the end of life. Ca(2+) is needed at several steps of the cell cycle such as early G(1), at the G(1)/S, and G(2)/M transitions. The Ca(2+) signals in the form of time-dependent changes in intracellular Ca(2+) concentrations, [Ca(2+)](i), are presented as brief spikes organized into regenerative Ca(2+) waves. Ca(2+)-mediated signaling pathways have also been shown to play important roles in c ...[more]

PMID: 20875431

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Project description:BackgroundPhosphotyrosine kinase (PTK)-mediated phospholipase C-γ1 (PLC-γ1) signaling plays a crucial role in the release of the universal second messenger calcium from intracellular stores, which is mandatory for several cellular processes, including cell migration. However, PLC-γ1 could also be activated in a PTK-independent manner by phospholipase D (PLD)-derived phosphatidic acid (PA). Because both higher PLD expression levels and PLD activity have also been associated with breast cancer cell invasion and migration, we wondered whether there might be a link between PLD and PLC-γ1, which was investigated in this study.MaterialsMDA-MB-468-NEO (EGFR positive) and MDA-MB-468-HER2 (EGFR and HER2 positive) human breast cancer cells were used in this study. The migratory behavior of the cells in the presence of epidermal growth factor (EGF) and the PLD inhibitor 5-fluoro-2-indolyl-des-chlorohalopemide (FIPI) was analyzed using the 3D collagen matrix migration assay. Changes in cytosolic calcium levels in the presence of EGF, FIPI and Sig-1R agonists and antagonists as well as in PLD1 siRNA knockdown cells were determined by flow cytometry. Western blot analyses were performed to determine the basal expression levels and phosphorylation patterns of EGFR, HER2, AKT, MAPKp42/44, PLC-γ1 and Sig-1R.ResultsThe EGF-induced migration of MDA-MB-468-NEO and MDA-MB-468-HER2 cells was significantly impaired by FIPI. Likewise, FIPI also significantly abolished EGF-induced calcium release in both cell lines. However, neither the expression levels nor the phosphorylation patterns of EGFR, HER2, AKT, MAPKp42/44 and PLC-γ1 were markedly changed by FIPI. Knockdown of PLD1 expression by siRNA also significantly impaired EGF-induced calcium release in both cell lines. Targeting Sig-1R, which interacts with IP3R, with the antagonist BD1047 also abrogated EGF-induced calcium release. However, EGF-induced calcium release was also impaired if cells were treated with the Sig-1R agonists PRE084 and PPBP maleate.ConclusionIn summary, blocking PLD activity with the specific inhibitor FIPI or knocking down PDL1 expression by siRNA significantly impaired EGF-induced calcium release in MDA-MB-468-NEO and MDA-MB-468-HER2 cells, likely indicating a connection between PLD activity and PLC-γ1-mediated calcium signaling. However, how PLD activity interferes with the release of calcium from intracellular stores remains unclear. Video Abstract.

Project description:Aggressive cellular phenotypes such as uncontrolled proliferation and increased migration capacity engender cellular transformation, malignancy and metastasis. While genetic mutations are undisputed drivers of cancer initiation and progression, it is increasingly accepted that external factors are also playing a major role. Two recently studied modulators of breast cancer are changes in the cellular mechanical microenvironment and alterations in calcium homeostasis. While many studies investigate these factors separately in breast cancer cells, very few do so in combination. This current work sets a foundation to explore mechano-calcium relationships driving malignant progression in breast cancer. Utilizing real-time imaging of an in vitro scratch assay, we were able to resolve mechanically-sensitive calcium signaling in human breast cancer cells. We observed rapid initiation of intracellular calcium elevations within seconds in cells at the immediate wound edge, followed by a time-dependent increase in calcium in cells at distances up to 500?m from the scratch wound. Calcium signaling to neighboring cells away from the wound edge returned to baseline within seconds. Calcium elevations at the wound edge however, persisted for up to 50 minutes. Rigorous quantification showed that extracellular calcium was necessary for persistent calcium elevation at the wound edge, but intercellular signal propagation was dependent on internal calcium stores. In addition, intercellular signaling required extracellular ATP and activation of P2Y2 receptors. Through comparison of scratch-induced signaling from multiple cell lines, we report drastic reductions in response from aggressively tumorigenic and metastatic cells. The real-time scratch assay established here provides quantitative data on the molecular mechanisms that support rapid scratch-induced calcium signaling in breast cancer cells. These mechanisms now provide a clear framework for investigating which short-term calcium signals promote long-term changes in cancer cell biology.

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Calcium wave signaling in cancer cells.

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Calcium wave signaling in cancer cells.

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