title: Expression of Clostridium perfringens enterotoxin receptors claudin-3 and claudin-4 in prostate cancer epithelium.
abstract: The mRNA for Rvp.1 (rat ventral prostate) increases in abundance before gland involution after androgen deprivation. Rvp.1 is homologous to CPE-R, the high-affinity intestinal epithelial receptor for Clostridium perfringens enterotoxin (CPE), and is sufficient to mediate CPE binding and trigger subsequent toxin-mediated cytolysis. Rvp.1 (claudin-3) and CPE-R (claudin-4) are members of a larger family of transmembrane tissue-specific claudin proteins that are essential components of intercellular tight junction structures regulating paracellular ion flux. However, claudin-3 and claudin-4 are the only family members capable of mediating CPE binding and cytolysis. The present study was designed to study the expression of claudin-3 and claudin-4 in human prostate tissue as potential targets for CPE toxin-mediated therapy for prostate cancer. On human multiple-tissue Northern blot analysis, mRNAs for both claudin-3 and claudin-4 were expressed at high levels in prostate tissue. In normal prostate tissue, expression of claudin-3 was localized exclusively within acinar epithelial cells by in situ mRNA hybridization. Compared with expression within prostate epithelial cells in surrounding normal glandular tissue, expression of claudin-3 mRNA remained high in the epithelium of prostate adenocarcinoma (10 of 10) and prostatic intraepithelial neoplasia (five of five). Prostate adenocarcinoma cells metastatic to bone were obtained from a patient with disease progression during antiandrogen therapy. These metastatic cells were prostate-specific antigen-positive by immunohistochemical staining and also expressed functional CPE receptors as measured by sensitivity to CPE-induced cell lysis. The persistent high level of claudin-3 expression in prostate adenocarcinoma and functional cytotoxicity of CPE in metastatic androgen-independent prostate adenocarcinoma suggests a new potential therapeutic strategy for prostate cancer.
authors.affiliation: Departments of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: H
authors.initials: H
authors.lastname: Long
authors.forename: C D
authors.initials: CD
authors.lastname: Crean
authors.forename: W H
authors.initials: WH
authors.lastname: Lee
authors.forename: O W
authors.initials: OW
authors.lastname: Cummings
authors.forename: T G
authors.initials: TG
authors.lastname: Gabig
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000556:secondary; D000728:Androgens / Q000502:physiology; D000818:Animals; D019046:Bone Marrow Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D002522:Chlorocebus aethiops; D062465:Claudin-3; D062506:Claudin-4; D003016:Clostridium perfringens / Q000235:genetics / Q000378:metabolism; D004768:Enterotoxins / Q000378:metabolism / Q000633:toxicity*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014709:Vero Cells
chemical_list: D000728:Androgens; C568122:CLDN3 protein, human; C568157:CLDN4 protein, human; D062465:Claudin-3; D062506:Claudin-4; C568124:Cldn3 protein, rat; D004768:Enterotoxins; D008565:Membrane Proteins; D012333:RNA, Messenger; C035598:enterotoxin, Clostridium