Androgen and the blocking of radiation‐induced sensitization to Fas‐mediated apoptosis through c‐jun induction in prostate cancer cells

Abstract

Purpose: To clarify the key mechanism by which androgen makes prostate cancer cells highly resistant to Fas‐mediated apoptosis.

Materials and methods: The role of c‐jun induction by 10 nM dihydrotestosterone (DHT) in 5 Gy radiation‐induced up‐regulation of Fas and sensitization to the apoptosis was studied by using the human prostate cancer cell line LNCaP.

Results: On exposure to 5 Gy radiation, LNCaP cells demonstrated high sensitization to Fas‐mediated apoptosis through increased Fas expression, stabilized p53 expression and binding to p53 response elements within the promoter and first intronic region of the Fas gene. Following treatment with DHT, in vivo binding of p53 to its response elements was strongly inhibited. In addition, DHT significantly up‐regulated c‐jun expression through extracellular stress‐regulated kinase (ERK) activation, and transfection of an antisense oligonucleotide for c‐jun or ERK inhibition by PD98059 cancelled DHT‐mediated suppression of radiation‐induced transactivation of Fas gene and sensitization to Fas‐mediated apoptosis.

Conclusions: Radiation‐induced Fas sensitization in prostate cancer cell was mediated through p53‐dependent transactivation of the Fas gene, which can be blocked by androgen stimulation mainly through induction of c‐jun.