TUMOR NECROSIS FACTOR-α REPRESSES ANDROGEN SENSITIVITY IN THE LNCaP PROSTATE CANCER CELL LINE

Abstract

No AccessJournal of UrologyINVESTIGATIVE UROLOGY1 Sep 2000TUMOR NECROSIS FACTOR-α REPRESSES ANDROGEN SENSITIVITY IN THE LNCaP PROSTATE CANCER CELL LINE ATSUSHI MIZOKAMI, AKINOBU GOTOH, HIROSHI YAMADA, EVAN T. KELLER, and TETSURO MATSUMOTO ATSUSHI MIZOKAMIATSUSHI MIZOKAMI More articles by this author , AKINOBU GOTOHAKINOBU GOTOH More articles by this author , HIROSHI YAMADAHIROSHI YAMADA More articles by this author , EVAN T. KELLEREVAN T. KELLER More articles by this author , and TETSURO MATSUMOTOTETSURO MATSUMOTO More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(05)67318-1AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: Prostate tumor progression is characterized by development of androgen independence and a heterogeneous distribution of the androgen receptor (AR). Tumor necrosis factor α (TNFα) has been demonstrated to contribute to the progression of several cancers and thus may play a role in prostate cancer progression. Accordingly, we examined if prostate cancers express TNFα and the effect of TNFα on androgen sensitivity and AR expression in LNCaP prostate cancer cells. Materials and Methods: Immunohistochemical analysis of prostate tissues, ELISA, and northern blotting of LNCaP cell lines were carried out for detection of tumor necrosis factor-α (TNFα). To see the effect of TNFα on androgen receptor (AR), western blotting and northern blotting were performed after extraction of total protein and total RNA from LNCaP cells. Regulation of androgen-sensitivity by TNFα was investigated with cell proliferation assay and luciferase assay using PSA promoter after transfection of LNCaP cells. Results: Immunohistochemical analysis demonstrated that TNFα protein was strongly expressed in epithelial cells of prostate cancer tissue but not in normal prostatic tissue. Basal level of TNFα in cell culture medium from LNCaP cells was very low. However, 12-O-tetradecanoylphorbol 13-acetate (TPA) induced TNFα secretion into medium up to 1600 pg/ml/day. Furthermore, 24 hr. post-TPA treatment TNFα mRNA levels were increased 15-fold compared to pre-treatment levels. TNFα (0 to 30 ng./ml. for 4 days) repressed AR protein and mRNA levels in a dose-dependent fashion in LNCaP cells. Pre-treatment of cells with actinomycin D treatment revealed that repression of mRNA levels was exerted at the post-transcriptional level. TNFα inhibited the ability of 10−9 M dihydrotestosterone (DHT) to induce LNCaP cell proliferation and activation of the prostate specific antigen (PSA) gene promoter. This inhibition was partially reversed by overexpression of transgenic androgen receptor. Conclusions: TNFα is present and inducible in prostate cancer cells and short-term TNFα diminishes androgen-sensitivity in LNCaP cells through down-regulation of AR protein and mRNA levels. These results suggest that TNFα may play a role in the initiation of an androgen-independent state in prostate cancer through its ability to inhibit AR sensitivity in prostate cancer. References 1 : Cancer statistics, 1994. CA Cancer J Clin1994; 44: 7. Google Scholar 2 : [Therapy of advanced prostatic cancer]. Wien Med Wochenschr1988; 138: 169. Google Scholar 3 : Immunohistochemistry of the androgen receptor in human benign and malignant prostate tissue. J Urol1993; 149: 1015. Link, Google Scholar 4 : Immunocytochemical assay for androgen receptors in prostate cancer: a prospective study of 63 cases with long-term follow-up. Ann Surg Oncol1994; 1: 495. 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Google Scholar From the Department of Urology, University of Occupational and Environmental Health, Kitakyushu-City, the Department of Urology, Kobe University, Chuo-ku, Kobe-City, Japan, the Unit for Laboratory Animal Medicine, Department of Pathology, Program in Cellular and Molecular Biology, and the Institute of Gerontology, University of Michigan, Ann Arbor, Michigan© 2000 by American Urological Association, Inc.FiguresReferencesRelatedDetailsCited byLUCIA M and TORKKO K (2018) Inflammation as a Target for Prostate Cancer Chemoprevention: Pathological and Laboratory RationaleJournal of Urology, VOL. 171, NO. 2S, (S30-S35), Online publication date: 1-Feb-2004. Volume 164Issue 3 Part 1September 2000Page: 800-805 Advertisement Copyright & Permissions© 2000 by American Urological Association, Inc.Keywordsprostate cancerTNFαandrogen sensitivityandrogen receptorMetricsAuthor Information ATSUSHI MIZOKAMI More articles by this author AKINOBU GOTOH More articles by this author HIROSHI YAMADA More articles by this author EVAN T. KELLER More articles by this author TETSURO MATSUMOTO More articles by this author Expand All Advertisement PDF downloadLoading ...