Genetic inactivation or pharmacological inhibition of Pdk1 delays development and inhibits metastasis of Braf(V600E)::Pten(-/-) melanoma.
Genetic inactivation or pharmacological inhibition of Pdk1 delays development and inhibits metastasis of Braf(V600E)::Pten(-/-) melanoma.
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磷酸肌醇依赖性激酶-1（PDK-1）是一种丝氨酸/苏氨酸蛋白激酶，可磷酸化保守的AGC激酶超家族成员，包括AKT和PKC，并参与重要的细胞过程，包括生存、代谢和肿瘤发生。在痣和黑色素瘤样本的大队列中，与痣相比，原发性黑色素瘤中的PDK 1表达显著更高，并且在转移性黑色素瘤中进一步增加。PDK 1的表达由于自身激活或磷酸肌醇3 '-OH-激酶（PI 3-K）的磷酸化升高而足以维持其活性。BrafV 600 E：：Pten−/−或BrafV 600 E：：Cdkn 2a −/−：：Pten−/−小鼠黑素细胞中Pdk 1的选择性失活延迟了全身或局部给予4-HT诱导的色素性病变和黑色素瘤的发展。黑色素瘤的侵袭和转移显着减少或完全阻止Pdk 1缺失。给予PDK 1抑制剂GSK 2334470（PDKi）可有效延迟BrafV 600 E：：Pten−/−小鼠的黑色素瘤发生和转移。Pdk 1 −/−黑色素瘤表现出AKT、P70 S6 K和PKC活性的显著降低。值得注意的是，PDKi在抑制AGC激酶和具有Pten WT基因型的黑素瘤的集落形成效率方面同样有效。基因表达分析确定了FOXO 3a调节基因中的Pdk 1依赖性变化，并且FOXO 3a的抑制恢复了Pdk 1 −/−黑素瘤细胞的增殖和集落形成。我们的研究为PDK 1的重要性提供了直接的遗传学证据，部分通过FOXO 3a依赖性途径，在黑色素瘤的发展和进展中发挥作用。
Phosphoinositide-dependent kinase-1 (PDK-1) is a serine/threonine protein kinase that phosphorylates members of the conserved AGC kinase superfamily, including AKT and PKC, and is implicated in important cellular processes including survival, metabolism and tumorigenesis. In large cohorts of nevi and melanoma samples, PDK1 expression was significantly higher in primary melanoma, compared with nevi, and was further increased in metastatic melanoma. PDK1 expression suffices for its activity, due to auto-activation, or elevated phosphorylation by phosphoinositide 3'-OH-kinase (PI 3-K). Selective inactivation of Pdk1 in the melanocytes of BrafV600E::Pten−/− or BrafV600E::Cdkn2a−/−::Pten−/− mice delayed the development of pigmented lesions and melanoma induced by systemic or local administration of 4-HT. Melanoma invasion and metastasis were significantly reduced or completely prevented by Pdk1 deletion. Administration of the PDK1 inhibitor GSK2334470 (PDKi) effectively delayed melanomagenesis and metastasis in BrafV600E::Pten−/− mice. Pdk1−/− melanomas exhibit a marked decrease in the activity of AKT, P70S6K and PKC. Notably, PDKi was as effective in inhibiting AGC kinases and colony forming efficiency of melanoma with Pten WT genotypes. Gene expression analyses identified Pdk1-dependent changes in FOXO3a-regulated genes and inhibition of FOXO3a restored proliferation and colony formation of Pdk1−/− melanoma cells. Our studies provide direct genetic evidence for the importance of PDK1, in part through FOXO3a-dependent pathway, in melanoma development and progression.
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影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
4
作者：
Huang, Haojie;Tindall, Donald J.
通讯作者：
Tindall, Donald J.
影响因子：
--
作者：
Shen, Hua;Zhu, Yu;Shu, Yong-Qian
通讯作者：
Shu, Yong-Qian
DOI：
10.1073/pnas.1004522107
发表时间：
2010-11-16
影响因子：
11.1
作者：
Miao, Benchun;Skidan, Igor;Degterev, Alexei
通讯作者：
Degterev, Alexei
影响因子：
11.2
作者：
Maurer M;Su T;Saal LH;Koujak S;Hopkins BD;Barkley CR;Wu J;Nandula S;Dutta B;Xie Y;Chin YR;Kim DI;Ferris JS;Gruvberger-Saal SK;Laakso M;Wang X;Memeo L;Rojtman A;Matos T;Yu JS;Cordon-Cardo C;Isola J;Terry MB;Toker A;Mills GB;Zhao JJ;Murty VV;Hibshoosh H;Parsons R
通讯作者：
Parsons R