Abstract A46: 3D cultured prostate organoids derived from PTEN-conditional KO mouse models of prostate cancer reveal Class IA PI3Kα drives tumorigenesis and the levels of its lipid products are pH dependent

PTEN公司 PI3K/AKT/mTOR通路 张力素 P110α 蛋白激酶B 磷脂酰肌醇 磷酸肌醇3激酶 癌变 生物 癌症研究 磷酸酶 激酶 抑癌基因 细胞生物学 磷酸化 信号转导 癌症 化学 遗传学
作者
Barzan A. Sadiq
出处
期刊:Cancer Research [American Association for Cancer Research]
卷期号:78 (10_Supplement): A46-A46
标识
DOI:10.1158/1538-7445.mousemodels17-a46
摘要

Abstract There are over a million new cases of prostate cancer annually in the world. In approximately 70% of the cases, at least one copy of the tumor suppressor gene, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), is found to be lost at diagnosis. PTEN is a phosphatase that works in contrast of the class I PI3Ks (phosphoinositide 3-kinase). Class I PI3Ks are heterodimers composed of a catalytic subunit (p110α, p110β, p110δ, or p110γ), which lend their names to the different PI3K complexes, and a regulatory subunit (p85α, p85β, p84, or p101). These heterodimers are expressed differently and seem to assume specific roles in different cellular functions, both within different tissues and single cell types, and are able to convey spatially restricted signals, by phosphorylating the PI(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) to produce PI(3,4,5)P3 (phosphatidylinositol 3,4,5-trisphosphate). These lipids belong to a complex signaling network widely implicated in human physiopathology. PI(3,4,5)P3 activates vital downstream proteins, namely Akt/PKB (protein kinase B), that are crucial for many cellular processes such as glucose metabolism, transcription, cell proliferation, cell migration, and apoptosis. The PI(3,4,5)P3 pool is controlled by the dephosphorylating abilities of PTEN, to produce PI(4,5)P2, and SHIP to produce PI(3,4)P2 (phosphatidylinositol 3,4-bisphosphate), respectively. PI(3,4)P2 is an important second messenger itself that can also activate Akt. The loss of PTEN causes unregulated PI3K/Akt signaling, which allows survival of prostate cancer cells and prevents apoptosis. We have made use of an established system to culture mouse prostate organoids from mouse models of prostate cancer. These mice have a site-specific deletion of the PTEN phosphatase gene. In these mouse models, deletion of PTEN leads to hyperplasic growth of epithelial cells, which at 6-8 weeks of age develops into prostate intraepithelial neoplasia, and eventually to adenocarcinoma by 4 months. Therefore, they are good cancer models of the prostate gland and thus present a good opportunity to study the mechanisms of the prostate cancer. PTEN-dKO tissue and organoids show a significant reduction in PTEN protein expression in the mouse prostate, and grow to a more condensed yet sizable cell mass, in comparison to the wild-type controls. We have used this model to dissect class I PI3K signaling isoform specificity in driving tumorigenesis in mice prostate cancer, as well inferring the levels of the PI(3,4,5)P3 and PI(3,4)P2 to establish a route in which these lipids play a role in the development and survival of prostatic cancerous cells. Our data indicate that there is a substantial increase in the accumulated levels of PI(3,4,5)P3 and PI(3,4)P2. We show that this is primarily driven by the class IA PI3Kα isoform. We further report that the levels of those two vital signaling lipids are dependent on the pH level of the tumor microenvironment. Furthermore, the vast accumulation of PI(3,4)P2 seen in the PTEN-dKO mouse prostate tissue and organoids suggest that PTEN may also be the primary phosphatase dephosphorylating the PI(3,4)P2 lipids. Our findings using the organoid system that are derived from mouse models of prostate cancer further our knowledge in understanding the mechanisms of this diseases to allow finding suitable targeted treatments for it. Note: This abstract was not presented at the conference. Citation Format: Barzan A. Sadiq. 3D cultured prostate organoids derived from PTEN-conditional KO mouse models of prostate cancer reveal Class IA PI3Kα drives tumorigenesis and the levels of its lipid products are pH dependent [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A46.

科研通智能强力驱动
Strongly Powered by AbleSci AI

祝大家在新的一年里科研腾飞
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
科研通AI2S应助研友_Zeg3VL采纳,获得10
刚刚
地质锤关注了科研通微信公众号
刚刚
4秒前
amlzh应助Soir采纳,获得20
5秒前
小金完成签到,获得积分20
6秒前
Hello应助whuijuan采纳,获得10
6秒前
8秒前
zsl发布了新的文献求助10
8秒前
上善若水完成签到,获得积分10
9秒前
9秒前
简单的沛蓝完成签到 ,获得积分10
12秒前
雪白砖家发布了新的文献求助20
12秒前
络桵完成签到,获得积分10
12秒前
13秒前
14秒前
123发布了新的文献求助10
14秒前
地质锤发布了新的文献求助10
14秒前
Lynn发布了新的文献求助10
15秒前
NexusExplorer应助郭郭采纳,获得10
18秒前
orixero应助忧郁的鱿鱼采纳,获得10
18秒前
WZQ发布了新的文献求助10
19秒前
你的样子完成签到,获得积分10
22秒前
雪白砖家完成签到,获得积分10
22秒前
科研通AI2S应助ggggggg采纳,获得30
23秒前
seeyou完成签到 ,获得积分10
24秒前
CipherSage应助友好的小鸽子采纳,获得10
24秒前
25秒前
25秒前
26秒前
WZQ完成签到,获得积分10
26秒前
sxy发布了新的文献求助10
28秒前
妮妮完成签到,获得积分10
28秒前
29秒前
郭郭发布了新的文献求助10
30秒前
英俊的铭应助Sunshine采纳,获得10
33秒前
善学以致用应助咿咿呀呀采纳,获得10
34秒前
无花果应助郭郭采纳,获得10
36秒前
所所应助下雨采纳,获得10
39秒前
39秒前
40秒前
高分求助中
Востребованный временем 2500
The Three Stars Each: The Astrolabes and Related Texts 1500
Very-high-order BVD Schemes Using β-variable THINC Method 990
Les Mantodea de Guyane 800
Mantids of the euro-mediterranean area 700
Field Guide to Insects of South Africa 660
Mantodea of the World: Species Catalog 500
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 物理化学 催化作用 细胞生物学 免疫学 冶金
热门帖子
关注 科研通微信公众号,转发送积分 3396690
求助须知:如何正确求助?哪些是违规求助? 3006279
关于积分的说明 8820307
捐赠科研通 2693354
什么是DOI,文献DOI怎么找? 1475314
科研通“疑难数据库(出版商)”最低求助积分说明 682394
邀请新用户注册赠送积分活动 675668