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Regulation of metastases by tumor suppressor INPP4B

肿瘤抑制因子 INPP4B 对转移的调节

基本信息

批准号：
8689539
负责人：
IRINA AGOULNIK
金额：
$ 41.81万
依托单位：
FLORIDA INTERNATIONAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-04 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8689539
关键词：
Ablation Affect Androgen Receptor Androgens Birds Breast Cancer Patient Castration Cell Line Cells Cessation of life Chromosomes, Human, Pair 10 Clinical Research Complement Data Development Disease Distant Embryo Environment Epithelial Cells Florida Gene Expression Profile Goals Hispanics Inositol International Invaded Laboratories Lead Ligands Lipids Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of prostate Mediating Metastasis Suppression Metastatic Prostate Cancer Minority Modeling Molecular Neoplasm Metastasis Organ PC3 cell line PTEN gene Pathway interactions Patients Pharmacotherapy Phosphatidylinositols Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Polyphosphates Prostate Prostatic Neoplasms Protein Tyrosine Phosphatase Protein phosphatase Receptor Signaling Recruitment Activity Recurrence Regulation Research Personnel Resistance Role Signal Pathway Signal Transduction Site Specificity Structure of capsule of prostate Students Therapeutic Time Tissue Microarray Training Tumor Suppressor Proteins Tyrosine Tyrosine Phosphorylation Universities anticancer research base bone cancer cell cancer recurrence design graduate student high risk malignant breast neoplasm metastatic process mutant neoplastic cell novel prevent prophylactic prostate cancer cell public health relevance standard of care tumor tumor progression undergraduate student

项目摘要

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.

描述（由申请人提供）：扩散到前列腺囊外的前列腺癌采用去势治疗，但最终失败，癌症复发，成为无法治愈的与去势无关的疾病。去势会导致 Akt 信号通路激活。我们发现 II 型肌醇多磷酸 4- 磷酸酶 (INPP4B) 通过减少 Thr308 和 Ser473 上的 Akt 磷酸化并消除 Akt1 总磷酸酪氨酸水平，直接拮抗前列腺癌细胞系中的 Akt 通路。我们还发现INPP4B是雄激素受体（AR）的直接靶标，因此在去势后会丢失。 INPP4B 在前列腺癌、乳腺癌和卵巢癌中充当肿瘤抑制因子，并且其表达在一半的癌症中缺失转移性前列腺癌。我们提出以下假设：雄激素消除会导致雄激素诱导的 INPP4B 表达丧失。 INPP4B 肿瘤抑制功能由其脂质和蛋白磷酸酶活性介导。 INPP4B 缺失会刺激 AR 和 Akt 信号通路，从而导致前列腺癌的复发。了解 INPP4B 如何调节这些途径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 INPP4B 肿瘤抑制功能的 INPP4B 催化活性。使用我们实验室中仅保留蛋白酪氨酸磷酸酶或仅保留脂质磷酸酶活性的几种突变体，我们将确定抑制转移所需的活性。目标 2. 确定 INPP4B 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 INPP4B 是否调节配体依赖性和配体非依赖性 AR 作用。我们还将确定不同 AR 活性的调节是否需要蛋白质酪氨酸磷酸酶或脂质磷酸酶活性，或两者都需要。目标 3. 确定转移过程中的哪些步骤受到 INPP4B 丢失的影响。我们将使用野生型和各种 INPP4B 突变体来阐明其转移抑制功能。我们将研究 INPP4B 在侵袭伪足形成中的作用，确定转移所需的催化活性，并确定受 INPP4B 损失影响的转移过程的步骤。我们将研究 INPP4B 缺失如何刺激 PCa 细胞转移、激活 Akt 并改变 AR 转录组。我们还将检查 INPP4B 活性在前列腺癌进展过程中是否发生变化。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

INPP4B is an oncogenic regulator in human colon cancer.

INPP4B 是人类结肠癌的致癌调节因子。

DOI：
10.1038/onc.2015.361
发表时间：
2016-06-09
期刊：
Oncogene
影响因子：
8
作者：
Guo ST;Chi MN;Yang RH;Guo XY;Zan LK;Wang CY;Xi YF;Jin L;Croft A;Tseng HY;Yan XG;Farrelly M;Wang FH;Lai F;Wang JF;Li YP;Ackland S;Scott R;Agoulnik IU;Hondermarck H;Thorne RF;Liu T;Zhang XD;Jiang CC
通讯作者：
Jiang CC

INPP4B suppresses prostate cancer cell invasion.

DOI：
10.1186/s12964-014-0061-y
发表时间：
2014-09-25
期刊：
Cell communication and signaling : CCS
影响因子：
0
作者：
Hodgson MC;Deryugina EI;Suarez E;Lopez SM;Lin D;Xue H;Gorlov IP;Wang Y;Agoulnik IU
通讯作者：
Agoulnik IU

Regulation of EZH2 Expression by INPP4B in Normal Prostate and Primary Prostate Cancer.

DOI：
10.3390/cancers15225418
发表时间：
2023-11-15
期刊：
CANCERS
影响因子：
5.2
作者：
Zhang, Manqi;Ceyhan, Yasemin;Mei, Shenglin;Hirz, Taghreed;Sykes, David B.;Agoulnik, Irina U.
通讯作者：
Agoulnik, Irina U.

Long-Lasting Consequences of Testosterone Exposure.

睾酮暴露的长期后果。