Neutrophil elastase and cancer

Satō, Takashi; Takahashi, Satoshi; Mizumoto, Takao; Harao, Michiko; Akizuki, Miwa; Takasugi, M; Fukutomi, Takashi; Yamashita, Jun‐ichi

doi:10.1016/j.suronc.2007.01.003

Cited by 113 publications

(92 citation statements)

References 22 publications

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“…A key functional test of this pathway was the demonstration that siRNA ablation of elastase production mimicked the cell-cycle response of I3C, demonstrating that the loss of elastase activity is sufficient to growth-arrest human breast cancer cells. Of the 3 general classes of human elastases that have been characterized (pancreatic, polymorphonuclear neutrophil, and metalloelastase), high levels of neutrophil elastase have been implicated in playing a critical role in the process of tumorigenesis of human breast cancers (32,33) and other cancers including nonsmall-cell lung carcinoma (40) and bladder cancer (41). In patients, high levels of elastase expression and/or activity in breast cancer tissue can be associated with poor clinical outcome, reduced survival rates (35,36), decreased responsiveness to chemotherapy (42), and reduced responsiveness to endocrine treatment (33,34).…”

Section: Discussionmentioning

confidence: 99%

“…The majority of the lowermolecular-weight cyclin E forms are derived from the proteolysis of the full-length 50-kDa cyclin E by intracellular serine proteases, such as elastase, which are expressed in most tissue types (27). Of the 3 general classes of human elastase that have been characterized [polymorphonuclear neutrophil elastase or leukocyte elastase, metalloelastase (or MMP12), and pancreatic elastase], the neutrophil elastase is highly expressed in human breast cancers and has been implicated in the processes of tumorigenesis (32). Importantly, the level and enzymatic activity of neutrophil elastase are an independent prognostic marker for breast cancer survival and clinical outcome as well as for metastasis progression of various cancers (33)(34)(35)(36).…”

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confidence: 99%

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The dietary phytochemical indole-3-carbinol is a natural elastase enzymatic inhibitor that disrupts cyclin E protein processing

Nguyen¹,

Aronchik²,

Brar³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Indole-3-carbinol (I3C), a naturally occurring component of Brassica vegetables, such as broccoli, cabbage, and Brussels sprouts, induces a G 1 cell-cycle arrest of human breast cancer cells, although the direct cellular targets that mediate this process are unknown. Treatment of highly invasive MDA-MB-231 breast cancer cells with I3C shifted the stable accumulation of cyclin E protein from the hyperactive lower-molecular-mass 35-kDa form that is associated with cancer cell proliferation and poor clinical outcomes to the 50-kDa cyclin E form that typically is expressed in normal mammary tissue. An in vitro cyclin E processing assay, in combination with zymography, demonstrated that I3C, but not its natural dimer, 3,3 -diindolylmethane, disrupts proteolytic processing of the 50-kDa cyclin E into the lower-molecular-mass forms by direct inhibition of human neutrophil elastase enzymatic activity. Analysis of elastase enzyme kinetics using either cyclin E or N-methoxysuccinyl-Ala-Ala-Pro-Val-p-nitroanalide as substrates demonstrated that I3C acts as a noncompetitive inhibitor of elastase activity with an inhibitory constant of Ϸ12 M. Finally, siRNA ablation of neutrophil elastase protein production in MDA-MB-231 cells mimicked the I3C-disrupted processing of the 50-kDa cyclin E protein and the indole-induced cell-cycle arrest. Taken together, our results demonstrate that elastase is the first identified specific target protein for I3C and that the direct I3C inhibition of elastase enzymatic activity implicates the potential use of this indole, or related compounds, in targeted therapies of human breast cancers where high elastase levels are correlated with poor prognosis.A critical challenge in controlling breast cancer is the identification of therapeutic agents that can effectively control the growth of both estrogen-responsive and nonresponsive breast cancer cells with reduced side effects, especially during prolonged treatments. Epidemiological studies show that frequent consumption of certain vegetables is associated with a lower incidence of cancers at various sites (1). For example, the consumption of Brassica (cruciferous) vegetables, such as cabbage, broccoli, and Brussels sprouts, is directly associated with decreased risk of reproductive tissue cancers in humans (2, 3) and reduced tumor incidence in experimental animals (4). These studies implicate the existence of specific biologically active phytochemicals that represent a largely untapped source of potent chemotherapeutic agents. One such promising molecule is indole-3-carbinol (I3C), a natural compound derived from glycobrassicin in Brassica vegetables, which has been shown to exhibit potent anticarcinogenic properties in a wide range of cancers such as lung, liver, colon, cervical, endometrial, prostate, and breast cancer (5-7). In addition, out of broad spectrum of analyzed phytochemicals, I3C was 1 of the few that tested positive as a chemopreventative agent in a panel of short-term bioassays relevant to carcinogen-induced DNA damage, tumor initiat...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

The dietary phytochemical indole-3-carbinol is a natural elastase enzymatic inhibitor that disrupts cyclin E protein processing

Nguyen¹,

Aronchik²,

Brar³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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show abstract

“…Insufficient levels of protease inhibitors has been therefore suggested as a contributing factor in a number of diseases including, among others, acute lung injury [2, 4, 5,], cystic fibrosis [6], ischemic reperfusion injury [7], rheumatoid arthritis [8], atherosclerosis [9], psoriasisT T [10] , and malignant tumors [11,12]. Moreover alpha-1 antitrypsin (α 1 -proteinase inhibitor) deficiency, an inherited disease, affects the lung and the liver.…”

Section: Introductionmentioning

confidence: 99%

The In Vitro Inhibition of Human Neutrophil Elastase Activity by some Yemeni Medicinal Plants

Alasbahi

2008

Sci Pharm

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“…Interest in neutrophil elastase during neoplastic processes stems from recent clinical reports that correlate elevated expression of this enzyme with poor survival rates in patients with primary breast cancer and non-small cell lung cancer. It also has recently been found to initiate development of acute promyelocytic leukemia (Naffra et al, 2009;Sato et al, 2006) Most serine proteinases are expressed by supporting tumor stromal cells, whereas membrane-anchored serine protease appear to be largely expressed by tumor cells at the cell surface and are thus ideally located to regulate cell-cell and cell-matrix interactions. Increasing evidence demonstrates that aberrant expression of enzymes such as matriptase and hepsin is a hallmark of several cancers and recent studies have defined molecular mechanisms underlying TTSP-promoted tumorigenesis, a processes causing carcinomas of skin, breast, and prostate (Choi et al, 2009).…”

Section: Serine Proteinasesmentioning

confidence: 99%