Knockdown of the cochaperone SGTA results in the suppression of androgen and PI3K/Akt signaling and inhibition of prostate cancer cell proliferation

Andrew P Trotta, Eleanor F Need, Luke A Selth, Samarth Chopra, Carole B Pinnock, Damien A Leach, Gerhard A Coetzee, Lisa M Butler, Wayne D Tilley, Grant Buchanan

    Research output: Contribution to journalArticlepeer-review

    14 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)2812-2823
    Number of pages12
    JournalInternational Journal of Cancer
    Volume133
    Issue number12
    DOIs
    Publication statusPublished - 15 Dec 2013

    Keywords

    • androgen signaling
    • kinase signaling
    • tetratricopeptide repeat cochaperones

    Fingerprint Dive into the research topics of 'Knockdown of the cochaperone SGTA results in the suppression of androgen and PI3K/Akt signaling and inhibition of prostate cancer cell proliferation'. Together they form a unique fingerprint.

    Cite this