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Endocrine Abstracts (2017) 49 OC7.5 | DOI: 10.1530/endoabs.49.OC7.5

1Florida International University, Miami, FL, USA; 2Nova Southeastern University, Ft. Lauderdale, FL, USA; 3Baylor College of Medicine, Houston, TX, USA.


Androgen receptor (AR) signaling is the main driver for prostate cancer progression and androgen ablation is the treatment of choice for tumors that spread beyond the prostate. Efficient at first, androgen ablation fails due in part to altered cell signaling and expression of AR spice variants. Cell signaling in prostate cancer is regulated by dual specificity phosphatases and tumor suppressors INPP4B and PTEN that are lost with prostate cancer progression. Loss of PTEN destabilizes AR and alters AR transcriptional output. We investigated how loss of INPP4B affects AR signaling. We have previously shown that AR induces expression of INPP4B in prostate cancer. Intriguingly, AR splice variant AR-V7, which also contributes to ADT resistance, was unable to induce INPP4B expression. We performed microarray analysis of changes in gene expression caused by INPP4B knockdown. Gene expression clustering and GSEA analysis revealed that the INPP4B loss significantly altered AR transcriptional activity. Using immunofluorescent labeling with 3D rendering we determined that INPP4B localizes to cellular and endoplasmic membranes. We and others have shown that INPP4B suppresses PI3K/Akt and PKC pathways. We show that INPP4B specifically inhibits PKCζ and βII in multiple prostate cancer cells. The analysis of PI3K, Akt and PKC specific inhibitors, LY294002, AZD5363, and BIM-I, showed that Akt and PKC signaling did contribute to the changes in AR signaling. We investigated INPP4B functions in prostates of Inpp4b−/− mice. AR expression in mouse prostate was not affected by the loss of INPP4B. Remarkably, expression of several direct AR target genes like Msmb, Apof, and Nkx3.1 was significantly reduced in Inpp4b−/− prostates. We compared Akt and PKC signaling in the anterior (AP), dorsal/lateral (DLP) and ventral (VP) prostate lobes of the wild-type and Inpp4b−/− mice. Loss of INPP4B increased Akt signaling in DLP and VP and PKC ζ and β II pathways in AP and DLP. We determined that levels of PTEN protein were unchanged in Inpp4b−/− mouse prostates suggesting that Akt signaling was elevated exclusively due to Inpp4b loss. Taken together, full length AR, but not AR-V7 induce INPP4B expression. INPP4B reciprocally modulates AR transcriptional activity without altering AR protein level in both normal prostate and prostate cancer cells and suppresses Akt and PKCζ and β II signaling and the suppression is required for optimal AR transcriptional activity.

Volume 49

19th European Congress of Endocrinology

Lisbon, Portugal
20 May 2017 - 23 May 2017

European Society of Endocrinology 

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