STAT3 enhances the constitutive activity of AGC kinases in melanoma by transactivating PDK1
STAT3 enhances the constitutive activity of AGC kinases in melanoma by transactivating PDK1
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DOI：
10.1186/s13578-018-0265-8
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发表时间：
2019-01-03
影响因子：
7.5
通讯作者：
Lopez-Bergami, Pablo
中科院分区：
文献类型：
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作者：
Elisa Picco, Maria;Victoria Castro, Maria;Lopez-Bergami, Pablo
研究背景PI 3 K/Akt和STAT 3信号通路在多种肿瘤中具有功能相关性。体外和体内研究都表明，STAT 3通路活性的生物化学或遗传操纵诱导Akt活性的相同方向的变化。然而，所涉及的机制一直不佳的特点。我们的目标是描述精确的机制连接STAT 3与Akt和其他AGC激酶的活性在癌症中使用黑色素瘤细胞作为model.ResultsWe表明，活性STAT 3组成型结合的PDK 1启动子和积极调节PDK 1转录通过两个STAT 3响应元件。用STAT 3-小发夹RNA转导WM 9和UACC 903黑色素瘤细胞降低PDK 1 mRNA和蛋白水平。STAT 3敲低也诱导AGC激酶Akt、PKC和SGK的磷酸化减少。STAT 3沉默对Akt磷酸化的抑制作用被HA-PDK 1恢复。沿着这条线，HA-PDK 1表达显著阻断了达卡巴嗪加STAT 3敲低诱导的细胞死亡。这种效果可能是由Bcl 2蛋白介导的，因为HA-PDK 1拯救Bcl 2，Bcl-XL，和Mcl 1水平下调后STAT 3 silencing.ConclusionsWe表明，PDK 1是STAT 3的转录靶点，连接STAT 3通路与AGC激酶在黑色素瘤中的活性。这些数据为在黑色素瘤和可能的其他恶性肿瘤中治疗靶向STAT 3和PDK 1的持续努力提供了进一步的理论基础。
BackgroundThe PI3K/Akt and the STAT3 pathways are functionally associated in many tumor types. Both in vitro and in vivo studies have revealed that either biochemical or genetic manipulation of the STAT3 pathway activity induce changes in the same direction in Akt activity. However, the implicated mechanism has been poorly characterized. Our goal was to characterize the precise mechanism linking STAT3 with the activity of Akt and other AGC kinases in cancer using melanoma cells as a model.ResultsWe show that active STAT3 is constitutively bound to the PDK1 promoter and positively regulate PDK1 transcription through two STAT3 responsive elements. Transduction of WM9 and UACC903 melanoma cells with STAT3-small hairpin RNA decreased both PDK1 mRNA and protein levels. STAT3 knockdown also induced a decrease of the phosphorylation of AGC kinases Akt, PKC, and SGK. The inhibitory effect of STAT3 silencing on Akt phosphorylation was restored by HA-PDK1. Along this line, HA-PDK1 expression significantly blocked the cell death induced by dacarbazine plus STAT3 knockdown. This effect might be mediated by Bcl2 proteins since HA-PDK1 rescued Bcl2, Bcl-XL, and Mcl1 levels that were down-regulated upon STAT3 silencing.ConclusionsWe show that PDK1 is a transcriptional target of STAT3, linking STAT3 pathway with AGC kinases activity in melanoma. These data provide further rationale for the ongoing effort to therapeutically target STAT3 and PDK1 in melanoma and, possibly, other malignancies.