Akt inhibitor MK-2206 promotes anti-tumor activity and cell death by modulation of AIF and Ezrin in colorectal cancer.
Akt inhibitor MK-2206 promotes anti-tumor activity and cell death by modulation of AIF and Ezrin in colorectal cancer.
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AKT抑制剂MK-2206通过调节结直肠癌的AIF和EZRIN促进抗肿瘤活性和细胞死亡。
DOI：
10.1186/1471-2407-14-145
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发表时间：
2014-03-01
期刊：
影响因子：
3.8
通讯作者：
Chowdhury S
中科院分区：
文献类型：
--
作者：
Agarwal E;Chaudhuri A;Leiphrakpam PD;Haferbier KL;Brattain MG;Chowdhury S
有大量证据表明异常细胞存活信号传导机制在癌症进展和转移中的作用。Akt是几种癌症中细胞存活信号机制的主要组成部分。研究表明，激活的Akt通过S87磷酸化稳定XIAP，导致生存素/XIAP复合物形成、半胱天冬酶抑制和癌细胞的细胞保护。我们已经报道了TGFβ/PKA/PP 2A介导的肿瘤抑制信号调节Akt磷酸化，与Survivin/XIAP复合物的解离相关，导致抑制应激依赖的细胞存活诱导。该研究使用了IGF 1 R依赖性结肠癌细胞（GEO和CBS）。在存在MK-2206的情况下测定对细胞增殖和细胞死亡的影响。进行异种移植研究以确定MK-2206对肿瘤体积的影响。通过蛋白质印迹分析确定对各种细胞死亡标志物如XIAP、存活素、AIF、Ezrin、pEzrin的影响。使用Graph pad 5.0进行统计分析。P < 0.05被认为是有意义的。我们的特点是一种新的Akt激酶抑制剂MK-2206诱导IGF 1 R依赖性结直肠癌（CRC）细胞的细胞死亡的机制与上调PI 3 K/Akt信号响应IGF 1 R激活。MK-2206治疗可显著降低体内肿瘤生长，并通过两种机制促进细胞死亡。这是第一份证明MK-2206导致Akt失活导致凋亡诱导因子（AIF）诱导和细胞核定位的报告，AIF参与非半胱天冬酶依赖性细胞死亡。我们还观察到暴露于MK-2206使T567位点的Ezrin去磷酸化，导致Akt-pEzrin-XIAP细胞存活信号传导的破坏。在该位点的埃兹蛋白磷酸化与实体瘤的恶性进展相关。这两种诱导细胞死亡的新机制的鉴定表明MK-2206可能是CRC中IGF 1 R依赖性癌症亚组治疗靶向的潜在临床候选药物。
There is extensive evidence for the role of aberrant cell survival signaling mechanisms in cancer progression and metastasis. Akt is a major component of cell survival-signaling mechanisms in several types of cancer. It has been shown that activated Akt stabilizes XIAP by S87 phosphorylation leading to survivin/XIAP complex formation, caspase inhibition and cytoprotection of cancer cells. We have reported that TGFβ/PKA/PP2A-mediated tumor suppressor signaling regulates Akt phosphorylation in association with the dissociation of survivin/XIAP complexes leading to inhibition of stress-dependent induction of cell survival. IGF1R-dependent colon cancer cells (GEO and CBS) were used for the study. Effects on cell proliferation and cell death were determined in the presence of MK-2206. Xenograft studies were performed to determine the effect of MK-2206 on tumor volume. The effect on various cell death markers such as XIAP, survivin, AIF, Ezrin, pEzrin was determined by western blot analysis. Graph pad 5.0 was used for statistical analysis. P < 0.05 was considered significant. We characterized the mechanisms by which a novel Akt kinase inhibitor MK-2206 induced cell death in IGF1R-dependent colorectal cancer (CRC) cells with upregulated PI3K/Akt signaling in response to IGF1R activation. MK-2206 treatment generated a significant reduction in tumor growth in vivo and promoted cell death through two mechanisms. This is the first report demonstrating that Akt inactivation by MK-2206 leads to induction of and mitochondria-to-nuclear localization of the Apoptosis Inducing Factor (AIF), which is involved in caspase-independent cell death. We also observed that exposure to MK-2206 dephosphorylated Ezrin at the T567 site leading to the disruption of Akt-pEzrin-XIAP cell survival signaling. Ezrin phosphorylation at this site has been associated with malignant progression in solid tumors. The identification of these 2 novel mechanisms leading to induction of cell death indicates MK-2206 might be a potential clinical candidate for therapeutic targeting of the subset of IGF1R-dependent cancers in CRC.
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影响因子：
3.7
作者：
Chowdhury S;Howell GM;Rajput A;Teggart CA;Brattain LE;Weber HR;Chowdhury A;Brattain MG
通讯作者：
Brattain MG
磷酸肌醇的结合和磷酸化在ezrin的激活机理中依次起作用。
影响因子：
7.8
作者：
Fievet, BT;Gautreau, A;Roy, C;Del Maestro, L;Mangeat, P;Louvard, D;Arpin, M
通讯作者：
Arpin, M
影响因子：
4.8
作者：
Chowdhury, Sanjib;Howell, Gillian M.;Brattain, Michael G.
通讯作者：
Brattain, Michael G.
影响因子：
5.3
作者：
Cheung, ECC;Melanson-Drapeau, L;Slack, RS
通讯作者：
Slack, RS
影响因子：
11.2
作者：
Hu YP;Patil SB;Panasiewicz M;Li W;Hauser J;Humphrey LE;Brattain MG
通讯作者：
Brattain MG