title: The co-chaperone p23 promotes prostate cancer motility and metastasis.
abstract: Prostate cancer is an androgen receptor (AR)-dependent malignancy at initiation and progression, therefore hormone therapy is the primary line of systemic treatment. Despite initial disease regression, tumours inevitably recur and progress to an advanced castration-resistant state a major feature of which is metastasis to the bone. Up-regulation of AR cofactors and chaperones that overcome low hormone conditions to maintain basal AR activity has been postulated as a mechanism of therapy relapse. p23, an essential component of the apo-AR complex, acts also after ligand binding to increase AR transcriptional activity and target gene expression, partly by increasing chromatin-loaded holo-receptor-complexes. Immunohistochemical studies have demonstrated increased p23 expression in advanced prostate cancer. Here, we further characterise p23 roles in AR signalling and show that it modulates cytosolic AR levels in the absence of hormone, confirming a chaperoning function in the aporeceptor complex and suggesting p23 upregulates AR signalling at multiple stages. Moreover, p23 protein levels significantly increased upon treatment with not only androgen but also clinically relevant anti-androgens. This was in contrast to the HSP90 inhibitor 17-AAG, which did not modulate expression of the cochaperone - important given the HSP90-independent roles we and others have previously described for p23. Further, we demonstrate p23 is implicated in prostate cancer cell motility and in acquisition of invasiveness capacity through the expression of specific genes known to participate in cancer progression. This may drive metastatic processes in vivo since analysis of prostate tumour biopsies revealed that high nuclear p23 significantly correlated with shorter survival times and with development of metastases in patients with lower grade tumours. We propose that increased p23 expression may allow cells to acquire a more aggressive phenotype, contributing to disease progression, and that p23 is a plausible secondary target in combination with HSP90 inhibition as a potential therapy for advanced prostate cancer.
authors.affiliation: Androgen Signalling Laboratory, Imperial Centre for Translational & Experimental Medicine, Imperial College London, London W12 0NN, UK.
authors.forename: Laia Querol
authors.initials: LQ
authors.lastname: Cano
authors.affiliation: Androgen Signalling Laboratory, Imperial Centre for Translational & Experimental Medicine, Imperial College London, London W12 0NN, UK.
authors.forename: Derek N
authors.initials: DN
authors.lastname: Lavery
authors.affiliation: Genetics Laboratory, Department of Tumor Biology, Institut Curie, Paris 75248, France.
authors.forename: Soraya
authors.initials: S
authors.lastname: Sin
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research and University Medical Centre Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
authors.forename: Emma
authors.initials: E
authors.lastname: Spanjaard
authors.affiliation: Androgen Signalling Laboratory, Imperial Centre for Translational & Experimental Medicine, Imperial College London, London W12 0NN, UK.
authors.forename: Greg N
authors.initials: GN
authors.lastname: Brooke
authors.affiliation: Androgen Signalling Laboratory, Imperial Centre for Translational & Experimental Medicine, Imperial College London, London W12 0NN, UK.
authors.forename: Jessica D
authors.initials: JD
authors.lastname: Tilman
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Abroaf
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK.
authors.forename: Luke
authors.initials: L
authors.lastname: Gaughan
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK.
authors.forename: Craig N
authors.initials: CN
authors.lastname: Robson
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Heer
authors.affiliation: Department of Histopathology, Imperial Healthcare NHS Trust, Hammersmith Hospital, London W12 0NN, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Mauri
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research and University Medical Centre Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: de Rooij
authors.affiliation: Genetics Laboratory, Department of Tumor Biology, Institut Curie, Paris 75248, France.
authors.forename: Keltouma
authors.initials: K
authors.lastname: Driouch
authors.affiliation: Androgen Signalling Laboratory, Imperial Centre for Translational & Experimental Medicine, Imperial College London, London W12 0NN, UK. Electronic address: charlotte.bevan@imperial.ac.uk.
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Bevan
mesh_terms: D016227:Benzoquinones / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008297:Male; D009362:Neoplasm Metastasis; D000071876:Prostaglandin-E Synthases; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C112765:tanespimycin; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases
keywords: Androgen receptor; Chaperone; Heat shock protein 90; Metastasis; Prostate cancer; p23