FOXO3a Regulates Glycolysis via Transcriptional Control of Tumor Suppressor TSC1
FOXO3a Regulates Glycolysis via Transcriptional Control of Tumor Suppressor TSC1
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DOI：
10.1074/jbc.m110.121871
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发表时间：
2010-05-21
影响因子：
4.8
通讯作者：
Plas, David R.
中科院分区：
文献类型：
--
作者：
Khatri, Shikha;Yepiskoposyan, Hasmik;Plas, David R.
Akt信号转导在广泛的癌症中诱导糖酵解和细胞凋亡抵抗的协调增加。在Akt的下游，FoxO转录因子通过Bim调节细胞凋亡，但FoxO在调节Akt诱导的糖酵解中的作用尚未得到很好的描述。我们发现FoxO3a敲低足以诱导细胞凋亡抵抗，同时糖酵解升高。foxo3a缺陷细胞中的糖酵解与S6K1磷酸化增加相关，并且对雷帕霉素敏感，雷帕霉素是mTORC1途径的抑制剂，与糖酵解调节有关。我们发现mTORC1依赖性糖酵解在FoxO3a敲除细胞中增加，这是由于抑制mTORC1激活的TSC1肿瘤抑制因子表达减少。FoxO3a结合并激活TSC1启动子，表明FoxO3a在调节TSC1表达中起关键作用。综上所述，这些数据表明FoxO3a通过转录控制Tsc1调控Akt下游的糖酵解。
Akt signal transduction induces coordinated increases in glycolysis and apoptosis resistance in a broad spectrum of cancers. Downstream of Akt, the FoxO transcription factors regulate apoptosis via Bim, but the contributions of FoxOs in regulating Akt-induced glycolysis are not well described. We find that FoxO3a knockdown is sufficient to induce apoptosis resistance in conjunction with elevated glycolysis. Glycolysis in FoxO3a-deficient cells was associated with increased S6K1 phosphorylation and was sensitive to rapamycin, an inhibitor of the mTORC1 pathway that has been linked to glycolysis regulation. We show that mTORC1-dependent glycolysis is increased in FoxO3a knockdown cells due to decreased expression of the TSC1 tumor suppressor that opposes mTORC1 activation. FoxO3a binds to and transactivates the TSC1 promoter, indicating a key role for FoxO3a in regulating TSC1 expression. Together, these data demonstrate that FoxO3a regulates glycolysis downstream of Akt through transcriptional control of Tsc1.