Long-term exposure of tumor necrosis factor ? causes hypersensitivity to androgen and anti-androgen withdrawal phenomenon in LNCaP prostate cancer cells

Abstract

BACKGROUND One of the mechanisms through which prostate cancers relapse during anti‐androgen therapy may involve adaptation to low concentrations of androgen induced by anti‐androgen therapies. Recent studies from our laboratory have reported that tumor necrosis factor‐α (TNFα) is secreted from prostate cancer epithelial cells and LNCaP cells. We hypothesized that TNFα changes androgen‐sensitivity in LNCaP cells. METHODS We cultured LNCaP cells for more than 3 months in the presence of 50 ng/ml TNFα and established TNFα‐resistant LNCaP cells (LN‐TR2). Sensitivity to androgen was examined by the cell proliferation assay. We also transfected LNCaP and LN‐TR2 cells with a luciferase reporter plasmid driven by prostate‐specific antigen (PSA) promoter and compared PSA promoter activity. Nuclear localization of AR protein that binds to target genes was also examined by Western blotting. RESULTS LN‐TR2 cells had increased sensitivity to dihydrotestosterone (DHT) (i.e., proliferation and PSA promoter activation) than LNCaP cells. Total AR mRNA and AR protein levels were decreased in LN‐TR2 cells. However, LN‐TR2 cells demonstrated increased levels of nuclear AR compared to LNCaP cells. At 1 nM DHT, the anti‐androgen bicalutamide stimulated LN‐TR2 and inhibited LNCaP proliferation. CONCLUSIONS Long‐term exposure of TNFα causes hypersensitivity to DHT in LNCaP and this was associated with increased nuclear AR protein. Furthermore, hypersensitivity to androgen caused anti‐androgen withdrawal phenomenon in the presence of DHT although bicalutamide itself did not stimulate LNCaP proliferation without androgen. This result may be one possible mechanism for the anti‐androgen withdrawal phenomenon. Prostate 46:319–326, 2001. © 2001 Wiley‐Liss, Inc.

The Transcriptional Co-Activator cAMP Response Element-Binding Protein-Binding Protein Is Expressed in Prostate Cancer and Enhances Androgen- and Anti-Androgen-Induced Androgen Receptor Function

“…44,45 Bicalutamide also enhanced the proliferation of a LNCaP subline generated after long-term treatment with tumor necrosis factor-␣ and, possibly, that effect was associated with the stimulation of AR activity. 46 The results of the present study do not rule out an involvement of CBP in those activation processes. Alternatively, one or more other AR co-activators might account for diminished antagonism of bicalutamide with HER-2/neu or ␤-catenin.…”

Vitamin D–induced up–regulation of tumour necrosis factor alpha (TNF–α) in prostate cancer cells

“…It regulates immune response and possesses antitumour activity (Tracey and Cerami, 1994;Beg and Baltimore, 1996). TNF-a was detected by immunohistochemical analysis as strongly expressed in epithelial cells of prostate cancer tissue as well as in TPAstimulated LNCaP cells (de Miguel et al, 2000;Mizokami et al, 2000;Harada et al, 2001). TNF-a seems to be involved in autocrine and paracrine regulation of cell growth in prostate cancer cells.…”

Androgen signaling and its interactions with other signaling pathways in prostate cancer

“…(81) Long-term exposure of TNFa induced androgen hypersensitivity in the LNCaP cells, which was associated with decreased levels of total AR, but increased nuclear AR levels. (82) Furthermore, there is mutual transcriptional repression between AR and NF-kB. (74) These data indicate differential crosstalk mechanisms between AR and TNF-a signaling in normal prostate cells and AR-positive and -negative prostate cancer cells.…”