title: Unexpected paracrine action of prostate cancer cells harboring a new class of androgen receptor mutation--a new paradigm for cooperation among prostate tumor cells.
abstract: The emergence of mutations in the androgen receptor (AR) gene is a recurrent event during progression of prostate cancer (PCa) on androgen ablation therapy. In this study, we show that nonsense mutations that lead to carboxyl-terminal end truncated ARs are found at high frequency in metastatic PCas. Transcriptional activities of the Q640X mutant AR in the androgen-sensitive LNCaP cell line differ to those of the wild-type AR. Indeed, this mutant AR exhibits strong and ligand-independent transcriptional activities from an artificial promoter construct containing two repeats of androgen-responsive elements, but is inactive on the human PSA gene promoter. Nevertheless, the expression of the Q640X mutant AR in LNCaP cells is accompanied by an increase in the level of PSA protein, and by an increase in the expression of the endogenous AR gene. This enhanced expression of the endogenous AR gene is not limited to the sole transfected cells, but is observed in non-transfected neighboring cells. Additionally, in co-cultures of transfected and non-transfected LNCaP cells, the Q640X mutant AR leads to an unpredicted nuclear localization of the endogenous AR protein in the two cellular populations and this, in the absence of androgen. These data indicate that cells expressing the Q640X mutant AR acquire the property to emit a signal that activates the AR in neighboring cells by a paracrine mechanism and in a ligand-independent manner. Our data strongly support the notion of cooperation among tumor cells in PCa and could be of relevance for the understanding of progression on androgen ablation therapy.
authors.affiliation: Université Strasbourg-Fac de Médecine, EA 3430-Signalisation et Cancer de la Prostate, Strasbourg, France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Lapouge
authors.forename: Eva
authors.initials: E
authors.lastname: Erdmann
authors.forename: Gemma
authors.initials: G
authors.lastname: Marcias
authors.forename: Monika
authors.initials: M
authors.lastname: Jagla
authors.forename: Audrey
authors.initials: A
authors.lastname: Monge
authors.forename: Pascal
authors.initials: P
authors.lastname: Kessler
authors.forename: Sebastian
authors.initials: S
authors.lastname: Serra
authors.forename: Hervé
authors.initials: H
authors.lastname: Lang
authors.forename: Didier
authors.initials: D
authors.lastname: Jacqmin
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bergerat
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Céraline
mesh_terms: D045744:Cell Line, Tumor; D018920:Coculture Techniques; D018389:Codon, Nonsense; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D008297:Male; D019899:Paracrine Communication / Q000502:physiology*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D017430:Prostate-Specific Antigen / Q000096:biosynthesis; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D011944:Receptors, Androgen / Q000235:genetics*; D014162:Transfection
chemical_list: D018389:Codon, Nonsense; D011944:Receptors, Androgen; D017430:Prostate-Specific Antigen