Perifosine-mediated Akt inhibition in neuroendocrine tumor cells: role of specific Akt isoforms

蛋白激酶B AKT2型 AKT1型 PI3K/AKT/mTOR通路 AKT3 癌症研究 磷酸化 细胞生物学 LY294002型 生物 化学 信号转导
作者
Kathrin Zitzmann,George Vlotides,Stephan Brand,Harald Lahm,Gerald Spöttl,Burkhard Göke,Christoph J. Auernhammer
出处
期刊:Endocrine-related Cancer [Bioscientifica]
卷期号:19 (3): 423-434 被引量:29
标识
DOI:10.1530/erc-12-0074
摘要

The majority of neuroendocrine tumors (NETs) of the gastroenteropancreatic system show aberrant Akt activity. Several inhibitors of the phosphoinositide 3-kinase (PI(3)K)–Akt–mTOR signaling pathway are currently being evaluated in clinical phase II and III studies for the treatment of NETs with promising results. However, the molecular mechanisms and particularly the role of different Akt isoforms in NET signaling are not fully understood. In this study, we examine the effect of Akt inhibition on NET cells of heterogeneous origin. We show that the Akt inhibitor perifosine effectively inhibits Akt phosphorylation and cell viability in human pancreatic (BON1), bronchus (NCI-H727), and midgut (GOT1) NET cells. Perifosine treatment suppressed the phosphorylation of Akt downstream targets such as GSK3α/β, MDM2, and p70S6K and induced apoptosis. To further investigate the role of individual Akt isoforms for NET cell function, we specifically blocked Akt1, Akt2, and Akt3 via siRNA transfection. In contrast to Akt2 knockdown, knockdown of Akt isoforms 1 and 3 decreased phosphorylation levels of GSK3α/β, MDM2, and p70S6K and suppressed NET cell viability and colony-forming capacity. The inhibitory effect of simultaneous downregulation of Akt1 and Akt3 on tumor cell viability was significantly stronger than that caused by downregulation of all Akt isoforms, suggesting a particular role for Akt1 and Akt3 in NET signaling. Akt3 siRNA-induced apoptosis while all three isoform-specific siRNAs impaired BON1 cell invasion. Together, our data demonstrate potent antitumor effects of the pan-Akt inhibitor perifosine on NET cells in vitro and suggest that selective targeting of Akt1 and/or Akt3 might improve the therapeutic potential of Akt inhibition in NET disease.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
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1L采纳,获得10
刚刚
1秒前
1秒前
刻苦熊猫应助无聊的三毒采纳,获得10
1秒前
OKAY完成签到,获得积分0
1秒前
2秒前
agrlook完成签到,获得积分10
2秒前
2秒前
2秒前
wyz完成签到,获得积分10
3秒前
苗苗会喵喵完成签到,获得积分10
3秒前
李健应助科研通管家采纳,获得20
3秒前
小二郎应助科研通管家采纳,获得10
3秒前
科研通AI2S应助科研通管家采纳,获得10
3秒前
pluto应助科研通管家采纳,获得10
3秒前
余余余完成签到,获得积分20
3秒前
无花果应助科研通管家采纳,获得10
3秒前
4秒前
小宇发布了新的文献求助10
4秒前
汉堡包应助小埋采纳,获得10
4秒前
4秒前
4秒前
4秒前
5秒前
xumengyu完成签到 ,获得积分10
5秒前
bimiracle完成签到,获得积分10
6秒前
阔达幼珊完成签到,获得积分10
6秒前
migratorybird发布了新的文献求助10
6秒前
ldjldj_2004发布了新的文献求助10
7秒前
兔子完成签到 ,获得积分10
7秒前
在望完成签到,获得积分10
7秒前
暄anbujun发布了新的文献求助10
7秒前
zengyan发布了新的文献求助20
8秒前
8秒前
Anthocyanidin完成签到,获得积分10
8秒前
Cammellia发布了新的文献求助10
9秒前
愉悦发布了新的文献求助10
9秒前
大卫发布了新的文献求助10
9秒前
搜集达人应助大魔王采纳,获得10
10秒前
A灰机发布了新的文献求助10
10秒前
高分求助中
Sustainability in Tides Chemistry 2800
The Young builders of New china : the visit of the delegation of the WFDY to the Chinese People's Republic 1000
юрские динозавры восточного забайкалья 800
English Wealden Fossils 700
Chen Hansheng: China’s Last Romantic Revolutionary 500
XAFS for Everyone 500
COSMETIC DERMATOLOGY & SKINCARE PRACTICE 388
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 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3143246
求助须知:如何正确求助?哪些是违规求助? 2794391
关于积分的说明 7811052
捐赠科研通 2450640
什么是DOI,文献DOI怎么找? 1303909
科研通“疑难数据库(出版商)”最低求助积分说明 627144
版权声明 601386