C16 ceramide accumulates following androgen ablation in LNCaP prostate cancer cells

Masatoshi Eto, Jaafar Bennouna, Oriana C. Hunter, Pamela A. Hershberger, Tatsuya Kanto, Candace S. Johnson, Michael T. Lotze, Andrew A. Amoscato

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

BACKGROUND. Adenocarcinoma of the prostate is the most frequently diagnosed noncutaneous cancer and the second leading cause of cancer-related deaths among men in the United States. The most successful therapies to date for this tumor have involved some form of androgen ablation. However, these therapies become ineffective as the tumor evolves to an androgen-insensitive state. Ceramide is a lipid second messenger that has been shown to mediate growth arrest or cell death when added exogenously to prostate cancer cells. As a first step toward understanding the events that lead to the transition of prostate cancer cells to an androgen-independent state, we considered investigating the effect of androgen ablation on endogenous ceramide levels in androgen-sensitive and androgen-insensitive prostate cancer cells. METHODS. To investigate the mechanisms of growth arrest/apoptosis in androgen-sensitive (LNCaP) and insensitive (DU-145, PC-3) cells, we used various methods including nonyl acridine orange (NAO) staining, propidium iodide (PI) staining/cell-cycle analysis, lipid analysis, and Western blotting assays. RESULTS. In this study, we demonstrate that androgen ablation drives G0/G1-phase cell-cycle arrest followed by progressive apoptosis in vitro, in LNCaP cells. Lipid analysis indicated an increase in C16 ceramide, which was generated via the de novo pathway as revealed by blockade of ceramide synthase by fumonisin B1. The addition of 5α-dihydrotestosterone (DHT) or fumonisin B1 rescued LNCaP cells from apoptosis induced by androgen ablation, and decreased levels of intracellular C16 ceramide. Neither apoptosis nor an increase in C16 ceramide was observed in androgen-independent cell lines following androgen ablation.

Original languageEnglish
Pages (from-to)66-79
Number of pages14
JournalProstate
Volume57
Issue number1
DOIs
Publication statusPublished - Sep 2003

All Science Journal Classification (ASJC) codes

  • Oncology
  • Urology

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