S6K1 deficiency protects against apoptosis in hepatocytes.
S6K1 deficiency protects against apoptosis in hepatocytes.
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DOI：
10.1002/hep.22915
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发表时间：
2009-07
期刊：
影响因子：
13.5
通讯作者：
Valverde, Angela M.
中科院分区：
文献类型：
--
作者：
Gonzalez-Rodriguez, Agueda;Alba, Javier;Zimmerman, Valeri;Kozma, Sara C.;Valverde, Angela M.
mTOR/S6K1 信号通路控制细胞生长和增殖。为了评估 S6K1 在肝脏死亡和存活之间平衡的重要性，我们从野生型和 S6K1 缺陷 (S6K1−/−) 小鼠中产生了永生化肝细胞系。在 S6K1−/− 肝细胞中，与野生型相比，caspase-8 和促凋亡蛋白 Bid 持续下调。此外，S6K1−/− 肝细胞未能对死亡受体激活的凋亡触发作出反应。在缺乏 S6K1 的细胞中，未观察到 TNFα 或抗 Fas 抗体 (Jo2) 导致的 caspase-8 激活和 FLIPL 降解。与野生型相比，Bid 裂解、细胞色素 C 释放、caspase-3 激活、DNA 梯带以及凋亡细胞百分比等下游事件均减弱。此外，抗凋亡蛋白 BclxL 在 TNFα 或 Jo2 处理的野生型肝细胞中下调，但这种反应在 S6K1−/− 细胞中被消除。在体内，S6K1 缺陷小鼠可以免受刀豆球蛋白 A 诱导的细胞凋亡的影响。生长因子的撤除强烈诱导野生型肝细胞凋亡，但不诱导 S6K1−/− 肝细胞凋亡。 S6K1 缺陷不会降低血清停药后的 BclxL/Bim 比率，从而保护细胞免受细胞色素 C 释放和 DNA 断裂的影响。在分子水平上，缺乏 S6K1 介导的负反馈会降低 IRS-1 丝氨酸磷酸化，从而激活磷脂酰肌醇 3-激酶 (PI 3-K)/Akt 和 ERK 介导的生存途径。然而，在联合 PI 3-K 或 ERK 抑制剂撤除血清后，S6K1−/− 肝细胞发生凋亡。这一发现可能解释了癌症治疗中对 mTOR 抑制剂的耐药机制，并强烈表明，抑制 S6K1 可以预防急性肝衰竭，并且与消除 Akt 和 ERK 持续激活的抑制剂联合使用，可以提高肝癌 (HCC) 治疗的疗效。
The mTOR/S6K1 signaling pathway controls cell growth and proliferation. To assess the importance of S6K1 in the balance between death and survival in the liver, we have generated immortalized hepatocyte cell lines from wild-type and S6K1-deficient (S6K1−/−) mice. In S6K1−/− hepatocytes caspase-8 and the pro-apoptotic protein Bid were constitutively down-regulated as compared to wild-type. Moreover, S6K1−/− hepatocytes failed to respond to the apoptotic trigger of death receptor activation. Neither caspase-8 activation nor FLIPL degradation in response to TNFα or anti-Fas antibody (Jo2) was observed in cells lacking S6K1. Downstream events such as Bid cleavage, cytochrome C release, caspase-3 activation, DNA laddering, as well as the percentage of apoptotic cells were attenuated as compared to wild-type. In addition, the anti-apoptotic protein BclxL was down-regulated in TNFα or Jo2-treated wild-type hepatocytes, but this response was abolished in S6K1−/−cells. In vivo, S6K1-deficient mice were protected against concanavalin A-induced apoptosis. The withdrawal of growth factors strongly induced apoptosis in wild-type, but not in S6K1−/− hepatocytes. S6K1 deficiency did not decrease BclxL/Bim ratio upon serum withdrawal, thereby protecting cells from cytochrome C release and DNA fragmentation. At the molecular level, the lack of S6K1-mediated negative feed-back decreased IRS-1 serine phosphorylation resulting in activation of survival pathways mediated by phosphatidylinositol 3-kinase (PI 3-K)/Akt and ERK. However, S6K1−/− hepatocytes underwent apoptosis upon serum withdrawal in combination of PI 3-K or ERK inhibitors. This finding might explain the mechanism of resistance to mTOR inhibitors in cancer treatments, and strongly suggests that the inhibition of S6K1 could protect against acute liver failure and, in combination with inhibitors that abrogate the sustained activation of Akt and ERK, could improve the efficacy of hepatocarcinoma (HCC) treatment.
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