Akt1 inhibition promotes breast cancer metastasis through EGFR-mediated β-catenin nuclear accumulation.
Akt1 inhibition promotes breast cancer metastasis through EGFR-mediated β-catenin nuclear accumulation.
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Akt1 抑制通过 EGFR 介导的 β-catenin 核积累促进乳腺癌转移
DOI：
10.1186/s12964-018-0295-1
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发表时间：
2018-11-16
期刊：
影响因子：
--
通讯作者：
Xie SQ
中科院分区：
文献类型：
--
作者：
Li W;Hou JZ;Niu J;Xi ZQ;Ma C;Sun H;Wang CJ;Fang D;Li Q;Xie SQ
Akt1基因的下调促进乳腺癌细胞上皮向间质转化。然而，其机制尚不完全清楚。方法采用免疫印迹法、免疫荧光法、荧光素酶法、实时PCR法、ELISA法和Matrigel侵袭法观察Akt1抑制对乳腺癌细胞的体外侵袭作用。采用小鼠肺转移模型，测定Akt抑制剂MK2206及其联合吉非替尼的体内疗效。结果Akt1基因下调可刺激β-连环蛋白核积累，导致乳腺癌细胞侵袭。Akt1抑制诱导的β-catenin核积累依赖于乳腺癌细胞中EGFR信号通路的延长激活。机制实验证明，Akt1的敲低通过PIKfyve在ser318位点的去磷酸化使PIKfyve失活，导致EGFR信号通路的降解减少。MK2206抑制Akt1可诱导乳腺癌细胞中EGFR和β-catenin的表达增加。此外，在小鼠肺转移模型中，低剂量的MK2206促进乳腺癌转移，而EGFR酪氨酸激酶抑制剂吉非替尼可能抑制Akt1抑制诱导的乳腺癌转移。结论egfr介导的β-catenin核积累对Akt1抑制诱导的乳腺癌转移至关重要。
BackgroundKnockdown of Akt1 promotes Epithelial-to-Mesenchymal Transition in breast cancer cells. However, the mechanisms are not completely understood.MethodsWestern blotting, immunofluorescence, luciferase assay, real time PCR, ELISA and Matrigel invasion assay were used to investigate how Akt1 inhibition promotes breast cancer cell invasion in vitro. Mouse model of lung metastasis was used to measure in vivo efficacy of Akt inhibitor MK2206 and its combination with Gefitinib.ResultsKnockdown of Akt1 stimulated β-catenin nuclear accumulation, resulting in breast cancer cell invasion. β-catenin nuclear accumulation induced by Akt1 inhibition depended on the prolonged activation of EGFR signaling pathway in breast cancer cells. Mechanistic experiments documented that knockdown of Akt1 inactivates PIKfyve via dephosphorylating of PIKfyve at Ser318site, resulting in a decreased degradation of EGFR signaling pathway. Inhibition of Akt1 using MK2206 could induce an increase in the expression of EGFR and β-catenin in breast cancer cells. In addition, MK2206 at a low dosage enhance breast cancer metastasis in a mouse model of lung metastasis, while an inhibitor of EGFR tyrosine kinase Gefitinib could potentially suppress breast cancer metastasis induced by Akt1 inhibition.ConclusionEGFR-mediated β-catenin nuclear accumulation is critical for Akt1 inhibition-induced breast cancer metastasis.
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影响因子：
16.6
作者：
Jacobsen K;Bertran-Alamillo J;Molina MA;Teixidó C;Karachaliou N;Pedersen MH;Castellví J;Garzón M;Codony-Servat C;Codony-Servat J;Giménez-Capitán A;Drozdowskyj A;Viteri S;Larsen MR;Lassen U;Felip E;Bivona TG;Ditzel HJ;Rosell R
通讯作者：
Rosell R
DOI：
10.1006/bbrc.2000.2471
发表时间：
2000-04-21
影响因子：
3.1
作者：
Dobrosotskaya, IY;James, GL
通讯作者：
James, GL
影响因子：
11.2
作者：
Li CW;Xia W;Lim SO;Hsu JL;Huo L;Wu Y;Li LY;Lai CC;Chang SS;Hsu YH;Sun HL;Kim J;Yamaguchi H;Lee DF;Wang H;Wang Y;Chou CK;Hsu JM;Lai YJ;LaBaff AM;Ding Q;Ko HW;Tsai FJ;Tsai CH;Hortobagyi GN;Hung MC
通讯作者：
Hung MC
影响因子：
3.8
作者：
Masuda, Hiroko;Zhang, Dongwei;Bartholomeusz, Chandra;Doihara, Hiroyoshi;Hortobagyi, Gabriel N.;Ueno, Naoto T.
通讯作者：
Ueno, Naoto T.
晚期前列腺癌中 Akt1-β-catenin 通路的抑制促进 TGF beta 1 介导的上皮间质转化和转移
影响因子：
9.7
作者：
Gao F;Alwhaibi A;Sabbineni H;Verma A;Eldahshan W;Somanath PR
通讯作者：
Somanath PR