title: Knockdown of the cochaperone SGTA results in the suppression of androgen and PI3K/Akt signaling and inhibition of prostate cancer cell proliferation.
abstract: Solid tumors have an increased reliance on Hsp70/Hsp90 molecular chaperones for proliferation, survival and maintenance of intracellular signaling systems. An underinvestigated component of the chaperone system is the tetratricopeptide repeat (TPR)-containing cochaperone, which coordinates Hsp70/Hsp90 involvement on client proteins as well as having diverse individual actions. A potentially important cochaperone in prostate cancer (PCa) is small glutamine-rich TPR-containing protein alpha (SGTA), which interacts with the androgen receptor (AR) and other critical cancer-related client proteins. In this study, the authors used small interfering RNA coupled with genome-wide expression profiling to investigate the biological significance of SGTA in PCa and its influence on AR signaling. Knockdown of SGTA for 72 hr in PCa C4-2B cells significantly altered expression of >1,900 genes (58% decreased) and reduced cell proliferation (p < 0.05). The regulation of 35% of 5α-dihydrotestosterone (DHT) target genes was affected by SGTA knockdown, with gene-specific effects on basal or DHT-induced expression or both. Pathway analysis revealed a role for SGTA in p53, generic PCa and phosphoinositol kinase (PI3K) signaling pathways; the latter evident by a reduction in PI3K subunit p100β levels and decreased phosphorylated Akt. Immunohistochemical analysis of 64 primary advanced PCa samples showed a significant increase in the AR:SGTA ratio in cancerous lesions compared to patient-matched benign prostatic hyperplasia tissue (p < 0.02). This study not only provides insight into the biological actions of SGTA and its effect on genome-wide AR transcriptional activity and other therapeutically targeted intracellular signaling pathways but also provides evidence for PCa-specific alterations in SGTA expression.
authors.affiliation: Cancer Biology Group, Freemasons Foundation Centre for Men's Health, Basil Hetzel Institute for Translational Health Research, Department of Medicine, University of Adelaide, Adelaide, Australia.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Trotta
authors.forename: Eleanor F
authors.initials: EF
authors.lastname: Need
authors.forename: Luke A
authors.initials: LA
authors.lastname: Selth
authors.forename: Samarth
authors.initials: S
authors.lastname: Chopra
authors.forename: Carole B
authors.initials: CB
authors.lastname: Pinnock
authors.forename: Damien A
authors.initials: DA
authors.lastname: Leach
authors.forename: Gerhard A
authors.initials: GA
authors.lastname: Coetzee
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Butler
authors.forename: Wayne D
authors.initials: WD
authors.lastname: Tilley
authors.forename: Grant
authors.initials: G
authors.lastname: Buchanan
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D049109:Cell Proliferation; D013196:Dihydrotestosterone / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D018832:Molecular Chaperones; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D011944:Receptors, Androgen / Q000032:analysis / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
chemical_list: D002352:Carrier Proteins; D013196:Dihydrotestosterone; D018832:Molecular Chaperones; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011944:Receptors, Androgen; D016159:Tumor Suppressor Protein p53; C114575:SGTA protein, human
keywords: androgen signaling; kinase signaling; tetratricopeptide repeat cochaperones