Abstract
BackgroundINPP4B and PTEN dual specificity phosphatases are frequently lost during progression of prostate cancer to metastatic disease. We and others have previously shown that loss of INPP4B expression correlates with poor prognosis in multiple malignancies and with metastatic spread in prostate cancer.ResultsWe demonstrate that de novo expression of INPP4B in highly invasive human prostate carcinoma PC-3 cells suppresses their invasion both in vitro and in vivo. Using global gene expression analysis, we found that INPP4B regulates a number of genes associated with cell adhesion, the extracellular matrix, and the cytoskeleton. Importantly, de novo expressed INPP4B suppressed the proinflammatory chemokine IL-8 and induced PAK6. These genes were regulated in a reciprocal manner following downregulation of INPP4B in the independently derived INPP4B-positive LNCaP prostate cancer cell line. Inhibition of PI3K/Akt pathway, which is highly active in both PC-3 and LNCaP cells, did not reproduce INPP4B mediated suppression of IL-8 mRNA expression in either cell type. In contrast, inhibition of PKC signaling phenocopied INPP4B-mediated inhibitory effect on IL-8 in either prostate cancer cell line. In PC-3 cells, INPP4B overexpression caused a decline in the level of metastases associated BIRC5 protein, phosphorylation of PKC, and expression of the common PKC and IL-8 downstream target, COX-2. Reciprocally, COX-2 expression was increased in LNCaP cells following depletion of endogenous INPP4B.ConclusionTaken together, we discovered that INPP4B is a novel suppressor of oncogenic PKC signaling, further emphasizing the role of INPP4B in maintaining normal physiology of the prostate epithelium and suppressing metastatic potential of prostate tumors.Electronic supplementary materialThe online version of this article (doi:10.1186/s12964-014-0061-y) contains supplementary material, which is available to authorized users.
Highlights
Inositol polyphosphate 4-phosphatase type II (INPP4B) and PTEN dual specificity phosphatases are frequently lost during progression of prostate cancer to metastatic disease
We demonstrated that Androgen receptor (AR) directly regulates expression of INPP4B in prostate cancer cells, suggesting that castration may lead to a decline in INPP4B and activation of V-akt murine thymoma viral oncogene homolog 1 (Akt) signaling [6]
We show that INPP4B expression causes downregulation of Protein kinase C (PKC) signaling, which in turn lowers expression of the proinflammatory cytokine interleukin 8 (IL-8) and its downstream target Cyclooxygenase 2 (COX-2)
Summary
INPP4B and PTEN dual specificity phosphatases are frequently lost during progression of prostate cancer to metastatic disease. We and others have previously shown that loss of INPP4B expression correlates with poor prognosis in multiple malignancies and with metastatic spread in prostate cancer. Understanding the pathways that regulate the metastatic process could facilitate identification of novel therapeutic targets to manage advanced prostate cancer. While castration therapy remains the primary treatment option for patients with metastatic prostate cancer, such therapies frequently fail and patients recur with castration-resistant metastatic disease. This suggests that castration itself activates pathways that lead to prostate cancer recurrence and metastases [4].
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