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Reaction-based fluorescent sensor for investigating mobile Zn2+ in mitochondria of healthy versus cancerous prostate cells.

ABSTRACT: Chelatable, mobile forms of divalent zinc, Zn(II), play essential signaling roles in mammalian biology. A complex network of zinc import and transport proteins has evolved to control zinc concentration and distribution on a subcellular level. Understanding the action of mobile zinc requires tools that can detect changes in Zn(II) concentrations at discrete cellular locales. We present here a zinc-responsive, reaction-based, targetable probe based on the diacetyled form of Zinpyr-1. The compound, (6-amidoethyl)triphenylphosphonium Zinpyr-1 diacetate (DA-ZP1-TPP), is essentially nonfluorescent in the metal-free state; however, exposure to Zn(II) triggers metal-mediated hydrolysis of the acetyl groups to afford a large, rapid, and zinc-induced fluorescence response. DA-ZP1-TPP is insensitive to intracellular esterases over a 2-h period and is impervious to proton-induced turn-on. A TPP unit is appended for targeting mitochondria, as demonstrated by live cell fluorescence imaging studies. The practical utility of DA-ZP1-TPP is demonstrated by experiments revealing that, in contrast to healthy epithelial prostate cells, tumorigenic cells are unable to accumulate mobile zinc within their mitochondria.

SUBMITTER: Chyan W

PROVIDER: S-EPMC3890804 | biostudies-other | 2014 Jan

REPOSITORIES: biostudies-other

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Reaction-based fluorescent sensor for investigating mobile Zn2+ in mitochondria of healthy versus cancerous prostate cells.

Chyan Wen W Zhang Daniel Y DY Lippard Stephen J SJ Radford Robert J RJ

Proceedings of the National Academy of Sciences of the United States of America 20131212 1

Chelatable, mobile forms of divalent zinc, Zn(II), play essential signaling roles in mammalian biology. A complex network of zinc import and transport proteins has evolved to control zinc concentration and distribution on a subcellular level. Understanding the action of mobile zinc requires tools that can detect changes in Zn(II) concentrations at discrete cellular locales. We present here a zinc-responsive, reaction-based, targetable probe based on the diacetyled form of Zinpyr-1. The compound, ...[more]

PMID: 24335702

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Project description:Background and study aims In the UK, over 40,000 patients are diagnosed with colorectal cancer each year1. Colonoscopy is an important diagnostic and therapeutic procedure in the management of colorectal cancer. The gold standard has been white-light endoscopy for screening the general population and for surveillance of patients at high risk of developing cancer. Early detection of colorectal lesions in screening has been shown to reduce colorectal cancer mortality. However, the detection of flat and depressed neoplasms presents a particular challenge. Recent developments to aid the detection and characterisation of dysplastic lesions include chromoendoscopy, narrow band imaging (NBI), auto-fluorescence (AFI) and confocal endomicroscopy. The development of an adjunct tool to specifically identify premalignant colorectal dysplasia and cancer, and to help distinguish between polyps. A key issue during transanal endoscopic microsurgery (TEMS) and endoscopic mucosal resection (EMR) is to determine where the resection margin should be. Based on conventional white light visualisation, it is often difficult to discern where that margin should be, particularly for flat or carpet-like lesions. A fluorescent tool that can highlight dysplastic tissue would therefore allow complete resection of abnormal tissue. Recent developments in molecular imaging include the generation of fluorescent probes. Lectins are specific carbohydrate recognition proteins and have previously been used to identify malignant tissue through changes in glycosylation observed in carcinogenesis. A detailed understanding of the changes in glycoprotein expression and glycosylation patterns that occur during carcinogenesis may help to identify potentially useful markers of dysplasia. Fluorescently labelled lectins therefore have the potential to distinguish dysplasia and cancer from normal mucosa, based on their differential binding. We have identified and used a fluorescently labelled lectin, Wisteria floribunda (WFA) as an adjunct endoscopic tool, which binds to normal mucosa, but not to high grade dysplasia or cancer. This lectin can also distinguish benign hyperplastic polyps (HPs) from pathologically significant polyps, including sessile serrated polyps (SSPs), traditional serrated adenomas (TSAs) and mucinous cancers. Our lectin can also identify areas of dysplasia in freshly resected ulcerative colitis and TEMS specimens. The lectin can be visualised using fluorescence-enabled endoscopes, e.g. ETMI (endoscopic Trimodal Imaging) colonoscopies. Who can participate? Adults aged 18 and older who are undergoing endoscopy procedures. What does the study involve? Participants who are undergoing endoscopy have their colonoscopy with white light as per standard practice. The fluorescent lectin is applied to any lesions identified with white light and an assessments are made on the fluorescence level. Where no lesions have been identified with white light, the fluorescent lectin is applied to a segment of colon to assess whether the lectin identifies any additional abnormalities. Following this their procedure is completed as per standard practice and the participant returns to recovery. Routine observations will be taken by the nursing staff and any side effects will be reported. Participants undergoing surgery are anaesthetised and positioned as per standard care. The lectin is applied to the lesion prior to excision and an assessment be made on its fluorescence. After excision, images aretaken of the resection margin. The procedure is completed. Following the procedure the surgeon is asked whether they would change the resection margin based on the appearance of the lectin, and this is compared to the histolopathologists reports of the margin. The participant returns to recovery and receive their routine care. All patients have their clinical notes reviewed 30 days post-procedure for any complications.

Dataset Information

Reaction-based fluorescent sensor for investigating mobile Zn2+ in mitochondria of healthy versus cancerous prostate cells.

Publications

Reaction-based fluorescent sensor for investigating mobile Zn2+ in mitochondria of healthy versus cancerous prostate cells.

Similar Datasets

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