INPP4B suppresses prostate cancer cell invasion

• Published in: Cell communication and signaling Vol. 12; no. 1; p. 61
• Main Authors: Hodgson, Myles C, Deryugina, Elena I, Suarez, Egla, Lopez, Sandra M, Lin, Dong, Xue, Hui, Gorlov, Ivan P, Wang, Yuzhuo, Agoulnik, Irina U
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 25-09-2014; BioMed Central
• Subjects: Animals; Biotechnology industry; Cancer; Care and treatment; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cloning; Colleges & universities; Cyclooxygenase 2 - metabolism; Development and progression; Diagnosis; Experiments; Gene expression; Gene Expression Regulation, Neoplastic; Genes; Genetic aspects; HEK293 Cells; Humans; Indoles - pharmacology; Inhibitor of Apoptosis Proteins - metabolism; Interleukin-8 - genetics; Interleukins; Male; Maleimides - pharmacology; Medical research; Metastasis; Mice, SCID; Neoplasm Invasiveness; p21-Activated Kinases - genetics; Patient outcomes; Phosphatase; Phosphatases; Phosphoric Monoester Hydrolases - genetics; Phosphoric Monoester Hydrolases - metabolism; Phosphorylation; Physiological aspects; Prevention; Prognosis; Prostate cancer; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - metabolism; Protein Kinase Inhibitors - pharmacology; Protein kinases; Proteins; RNA, Small Interfering - genetics; United States; California
• ISSN: 1478-811X; 1478-811X
• DOI: 10.1186/s12964-014-0061-y

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.
We 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.
Taken 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.