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Zn²⁺ influx activates ERK and Akt signaling pathways.

ABSTRACT: Zinc (Zn²⁺) is an essential metal in biology, and its bioavailability is highly regulated. Many cell types exhibit fluctuations in Zn²⁺ that appear to play an important role in cellular function. However, the detailed molecular mechanisms by which Zn²⁺ dynamics influence cell physiology remain enigmatic. Here, we use a combination of fluorescent biosensors and cell perturbations to define how changes in intracellular Zn²⁺ impact kinase signaling pathways. By simultaneously monitoring Zn²⁺ dynamics and kinase activity in individual cells, we quantify changes in labile Zn²⁺ and directly correlate changes in Zn²⁺ with ERK and Akt activity. Under our experimental conditions, Zn²⁺ fluctuations are not toxic and do not activate stress-dependent kinase signaling. We demonstrate that while Zn²⁺ can nonspecifically inhibit phosphatases leading to sustained kinase activation, ERK and Akt are predominantly activated via upstream signaling and through a common node via Ras. We provide a framework for quantification of Zn²⁺ fluctuations and correlate these fluctuations with signaling events in single cells to shed light on the role that Zn²⁺ dynamics play in healthy cell signaling.

SUBMITTER: Anson KJ

PROVIDER: S-EPMC7980380 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Zn2+ influx activates ERK and Akt signaling pathways.

Anson Kelsie J KJ Corbet Giulia A GA Palmer Amy E AE

Proceedings of the National Academy of Sciences of the United States of America 20210301 11

Zinc (Zn2+) is an essential metal in biology, and its bioavailability is highly regulated. Many cell types exhibit fluctuations in Zn2+ that appear to play an important role in cellular function. However, the detailed molecular mechanisms by which Zn2+ dynamics influence cell physiology remain enigmatic. Here, we use a combination of fluorescent biosensors and cell perturbations to define how changes in intracellular Zn2+ impact kinase signaling pathwa ...[more]

PMID: 33712543

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Project description:BackgroundColon cancer (CC) ranks the second highest mortality rate among malignant tumors worldwide, and the current mainstream treatment regimens are not very effective. The unique efficacy of Chinese herb medicine (CHM) for cancer has recently attracted increasing attention. Cinnamomi Ramulus (CR), as a classic CHM, has been widely used in the treatment of a variety of diseases for hundreds of years in China, but its specific pharmacological mechanism against CC needs to be fully evaluated.MethodsTCMSP and China National Knowledge Infrastructure database were utilized to predict the candidate ingredients of CR, and TCMSP and SwissTargetPrediction database were also employed to predict the drug targets of the candidate ingredients from CR. We subsequently evaluated the therapeutic effect of CR by orally administrating it on CC-bearing mice. Next, we further identified the potential CC-related targets by using Gene Expression Omnibus (GEO) database. Based on these obtained targets, the drug/disease-target PPI networks were constructed using Bisogenet plugin of Cytoscape. The potential core therapeutic targets were then identified through topological analysis using CytoNCA plugin. GO and KEGG enrichment analyses were performed to predict the underlying mechanism of CR against CC. Furthermore, these in silico analysis results were validated by a series of cellular functional and molecular biological assays. UPLC-MS/MS method and molecular docking analysis were employed to identify the potential key components from CR.ResultsIn this study, we firstly found that CR has potential therapeutic effect on cancer. Then, oral administration of CR could inhibit the growth of CC cells in C57BL/6 mice, while inhibiting the viability and motility of CC cells in vitro. We obtained 111 putative core therapeutic targets of CR. Subsequent enrichment analysis on these targets showed that CR could induce apoptosis and cell cycle arrest in CC cells by blocking Akt/ERK signaling pathways, which was further experimentally verified. We identified 5 key components from the crude extract of CR, among which taxifolin was found most likely to be the key active component against CC.ConclusionsOur results show that CR as well as its active component taxifolin holds great potential in treatment of CC.

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Zn²⁺ influx activates ERK and Akt signaling pathways.

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Zn<sup>2+</sup> influx activates ERK and Akt signaling pathways.

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