Pharmaceutical Sciences Faculty Publications

An Antiproliferative Factor from Interstitial Cystitis Patients is a Frizzled 8 Protein-Related Sialoglycopeptide

Document Type

Article

Publication Date

8-10-2004

Journal Title

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

ISSN

0027-8424

Volume

101

Issue

32

First Page

11803

Last Page

11808

DOI

10.1073/pnas.0404509101

PubMed ID

15282374

PubMed Central® ID

PMC511055

Abstract

Approximately 1 million people in the United States suffer from interstitial cystitis, a chronic painful urinary bladder disorder characterized by thinning or ulceration of the bladder epithelial lining; its etiology is unknown. We have identified a glycosylated frizzled-related peptide inhibitor of cell proliferation that is secreted specifically by bladder epithelial cells from patients with this disorder. This antiproliferative factor (APF) profoundly inhibits bladder cell proliferation by means of regulation of cell adhesion protein and growth factor production. The structure of APF was deduced by using ion trap mass spectrometry (MS), enzymatic digestion, lectin affinity chromatography, and total synthesis, and confirmed by coelution of native and synthetic APF derivatives on microcapillary reversed-phase liquid chromatography (microRPLC)/MS. APF was determined to be an acidic, heat-stable sialoglycopeptide whose peptide chain has 100% homology to the putative sixth transmembrane domain of frizzled 8. Both synthetic and native APF had identical biological activity in normal bladder epithelial cells and T24 bladder cancer cells. Northern blot analysis indicated binding of a probe containing the sequence for the frizzled 8 segment with mRNA extracted from cells of patients with interstitial cystitis but not controls. APF is therefore a frizzled-related peptide growth inhibitor shown to contain exclusively a transmembrane segment of a frizzled protein and is a potential biomarker for interstitial cystitis.

Keywords

Antineoplastic agents, cell adhesion molecules, cell division, cell line, tumor, chromatography, high pressure liquid, cystitis, interstitial, epithelial cells, glycoproteins, growth substances, mass spectrometry, molecular structure, peptide fragments, RNA, messenger, sialoglycoproteins, urinary bladder diseases

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