FAM83B-mediated activation of PI3K/AKT and MAPK signaling cooperates to promote epithelial cell transformation and resistance to targeted therapies.
FAM83B-mediated activation of PI3K/AKT and MAPK signaling cooperates to promote epithelial cell transformation and resistance to targeted therapies.
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DOI：
10.18632/oncotarget.1027
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发表时间：
2013-05
期刊：
影响因子：
--
通讯作者：
Jackson MW
中科院分区：
文献类型：
--
作者：
Cipriano R;Miskimen KL;Bryson BL;Foy CR;Bartel CA;Jackson MW
针对MAPK和AKT/mTOR信号的治疗目前正在对几种肿瘤类型的临床试验中进行评估。然而，最近的研究表明，由于获得性癌细胞耐药性以及正常细胞和癌细胞之间的治疗指数较小，这些治疗方法可能是有限的。识别参与MAPK或AKT/mTOR信号转导并在正常细胞和癌细胞之间差异表达的新蛋白将为机制上不同的治疗靶点提供潜在的抑制这些关键的癌症相关途径的可能性。我们最近发现FAM83B是一个新的、以前未被鉴定的癌基因，能够过度激活MAPK和mTOR信号并驱动永生化的人乳腺上皮细胞(HMEC)的致瘤性。我们在这里表明，FAM83B的高表达还激活了PI3K/AKT信号通路，并降低了对PI3K、AKT和mTOR抑制剂的敏感性。FAM83B与PI3K的p85α和p110α亚基以及AKT共沉淀，并增加P110α和AKT的膜定位，与PI3K/AKT信号的升高一致。在FAM83B表达升高的肿瘤细胞中，去除FAM83B降低了p110α和AKT膜的定位，抑制了AKT的磷酸化，并降低了体内的增殖、免疫球蛋白和致瘤性。我们认为，当使用针对MAPK和AKT/mTOR信号的联合治疗时，FAM83B的表达水平可能是一个重要的考虑因素。此外，FAM83B是一个新的癌基因，它完整地参与了PI3K/AKT和MAPK的激活，为未来针对FAM83B的治疗提供了基础，以抑制PI3K/AKT和MAPK驱动的癌症的生长。
Therapies targeting MAPK and AKT/mTOR signaling are currently being evaluated in clinical trials for several tumor types. However, recent studies suggest that these therapies may be limited due to acquired cancer cell resistance and a small therapeutic index between normal and cancer cells. The identification of novel proteins that are involved in MAPK or AKT/mTOR signaling and differentially expressed between normal and cancer cells will provide mechanistically distinct therapeutic targets with the potential to inhibit these key cancer-associated pathways. We recently identified FAM83B as a novel, previously uncharacterized oncogene capable of hyperactivating MAPK and mTOR signaling and driving the tumorigenicity of immortalized human mammary epithelial cells (HMEC). We show here that elevated FAM83B expression also activates the PI3K/AKT signaling pathway and confers a decreased sensitivity to PI3K, AKT, and mTOR inhibitors. FAM83B co-precipitated with the p85α and p110α subunits of PI3K, as well as AKT, and increased p110α and AKT membrane localization, consistent with elevated PI3K/AKT signaling. In tumor-derived cells harboring elevated FAM83B expression, ablation of FAM83B decreased p110α and AKT membrane localization, suppressed AKT phosphorylation, and diminished proliferation, AIG, and tumorigenicity in vivo. We propose that the level of FAM83B expression may be an important factor to consider when combined therapies targeting MAPK and AKT/mTOR signaling are used. Moreover, the identification of FAM83B as a novel oncogene and its integral involvement in activating PI3K/AKT and MAPK provides a foundation for future therapies aimed at targeting FAM83B in order to suppress the growth of PI3K/AKT- and MAPK-driven cancers.
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影响因子：
14.8
作者：
Scott, Sarah A.;Selvy, Paige E.;Buck, Jason R.;Cho, Hyekyung P.;Criswell, Tracy L.;Thomas, Ashley L.;Armstrong, Michelle D.;Arteaga, Carlos L.;Lindsley, Craig W.;Brown, H. Alex
通讯作者：
Brown, H. Alex
影响因子：
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作者：
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通讯作者：
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影响因子：
15.9
作者：
Cipriano, Rocky;Graham, James;Jackson, Mark W.
通讯作者：
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影响因子：
11.2
作者：
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通讯作者：
Jackson, Mark W.
影响因子：
15.9
作者：
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通讯作者：
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