Regulation of metastases by tumor suppressor INPP4B

描述（由申请人提供）：扩散到前列腺包膜以外的前列腺癌采用去势治疗，最终失败，癌症复发，成为不可治愈的去势非依赖性疾病。去势导致Akt信号通路的激活。我们发现，肌醇多磷酸4-磷酸酶II型（INPP 4 B）直接拮抗前列腺癌细胞系中的Akt途径，通过减少Akt磷酸化的Thr 308和Ser 473，并取消Akt 1总磷酸酪氨酸水平。我们还发现INPP 4 B是雄激素受体（AR）的直接靶点，因此在去势后会丢失。INPP 4 B在前列腺癌、乳腺癌和卵巢癌中作为肿瘤抑制因子，其表达在所有癌症中有一半丢失。 转移性前列腺癌我们提出以下假设：雄激素消融导致雄激素诱导的INPP 4 B表达的丧失。INPP 4 B肿瘤抑制剂功能由其脂质和蛋白磷酸酶活性介导。INPP 4 B缺失刺激AR和Akt信号通路，从而促进前列腺癌的复发。了解INPP 4 B如何调节这些通路将有助于发现新的药物治疗靶点，以预防或延迟转移。 目标1.表征定义INPP 4 B肿瘤抑制功能的INPP 4 B催化活性。使用几个突变体的特点，在我们的实验室，保留只有蛋白酪氨酸磷酸酶或只有脂质磷酸酶的活动，我们将确定需要抑制转移。 目标2.确定INPP 4 B对配体依赖性和配体非依赖性AR信号传导的影响。使用雄激素依赖性和雄激素非依赖性细胞系，我们将检查INPP 4 B是否调节配体依赖性和配体非依赖性AR作用。我们还将确定是否蛋白酪氨酸磷酸酶或脂质磷酸酶的活动，或两者兼而有之，需要不同的AR活动的调节。 目标3.确定转移过程中的哪些步骤受到INPP 4 B丢失的影响。我们将使用野生型和各种INPP 4 B突变体来阐明其转移抑制功能。我们将研究INPP 4 B在侵袭伪足形成中的作用，确定转移所必需的催化活性，并确定受INPP 4 B损失影响的转移过程的步骤。我们将研究INPP 4 B丢失如何刺激PCa细胞的转移，激活Akt并改变AR转录组。我们还将检查INPP 4 B活性在前列腺癌进展过程中是否发生变化。

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.