Regulation of metastases by tumor suppressor INPP4B

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DESCRIPTION (provided by applicant): Prostate cancer that spreads beyond the prostate capsule is treated with castration, which eventually fails and the cancer recurs as incurable castration-independent disease. Castration leads to activation the Akt signaling pathway. We found that inositol polyphosphate 4- phosphatase type II (INPP4B) directly antagonizes the Akt pathway in prostate cancer cell lines by decreasing Akt phosphorylation on Thr308 and Ser473, and abolishing Akt1 total phospho-tyrosine levels. We also discovered that INPP4B is a direct target of androgen receptor (AR) and thus would be lost after castration. INPP4B acts as a tumor suppressor in prostate, breast, and ovarian cancers and its expression is lost in half of all metastatic prostate cancers. We propose the following hypothesis: Androgen ablation leads to the loss of androgen-induced INPP4B expression. INPP4B tumor suppressor functions are mediated by its lipid and protein phosphatase activity. INPP4B loss stimulates AR and Akt signaling pathways, thus contributing to the recurrence of prostate cancer. Understanding how INPP4B regulates these pathways will help to uncover novel drug therapy targets to prevent or delay metastases. Aim 1. Characterize INPP4B catalytic activities that define INPP4B tumor suppressive function. Using several mutants characterized in our laboratory that retain only protein tyrosine phosphatase or only lipid phosphatase activities, we will determine which activity is required to suppress metastases. Aim 2. Determine the effect of INPP4B on ligand-dependent and ligand-independent AR signaling. Using androgen-dependent and androgen-independent cell lines, we will examine whether INPP4B regulates ligand-dependent and ligand-independent AR action. We will also determine whether protein tyrosine phosphatase or lipid phosphatase activities, or both, are required for the regulation of different AR activities. Aim 3. Establish which steps in the metastatic process are affected by loss of INPP4B. We will use wild-type and various INPP4B mutants to elucidate its metastasis-inhibiting function. We will examine the role of INPP4B in invadopodia formation, determine the catalytic activity essential for metastasis, and determine the steps of the metastatic process that are affected by INPP4B loss. We will examine how INPP4B loss stimulates metastases in PCa cells, activates Akt, and alters the AR transcriptome. We will also examine if INPP4B activity changes during prostate cancer progression.