Simian Virus 40 Small T Antigen Activates AMPK and Triggers Autophagy To Protect Cancer Cells from Nutrient Deprivation
Simian Virus 40 Small T Antigen Activates AMPK and Triggers Autophagy To Protect Cancer Cells from Nutrient Deprivation
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DOI：
10.1128/jvi.00603-09
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发表时间：
2009-09-01
影响因子：
5.4
通讯作者：
Rangarajan, Annapoorni
中科院分区：
文献类型：
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作者：
Kumar, Sravanth Hindupur;Rangarajan, Annapoorni
随着肿瘤越来越大，它们经常会遇到氧气和营养供应不足的情况。因此，癌细胞必须发展机制来克服这些压力。使用体外转化模型，其中猴病毒40（SV 40）小T（ST）抗原的存在已被证明是致瘤性转化的关键，我们研究了ST抗原是否在调节癌细胞的能量稳态中发挥作用。我们发现表达SV 40 ST抗原的细胞（+ST细胞）比缺乏SV 40 ST抗原的细胞（-ST细胞）对葡萄糖剥夺诱导的细胞死亡更具抵抗力。从机制上讲，我们发现ST抗原通过激活营养敏感激酶，AMP激活蛋白激酶（AMPK）介导这种效应。基础水平的活性，磷酸化AMPK是在+ST细胞高于-ST细胞，这些水平进一步增加，响应于葡萄糖剥夺。此外，在葡萄糖剥夺条件下，+ST细胞中AMPK的抑制增加了细胞死亡率，而-ST细胞中AMPK的激活降低了细胞死亡率。我们进一步表明，AMPK介导其作用，至少部分，通过抑制mTOR（哺乳动物雷帕霉素靶蛋白），从而关闭蛋白质翻译。最后，我们发现+ST细胞在葡萄糖剥夺后表现出比-ST细胞更高的自噬百分比。因此，我们证明了SV 40 ST抗原在癌症中的新作用，其中它的功能是通过激活AMPK，抑制mTOR和诱导自噬作为替代能源来维持葡萄糖剥夺期间的能量稳态。
As tumors grow larger, they often experience an insufficient supply of oxygen and nutrients. Hence, cancer cells must develop mechanisms to overcome these stresses. Using an in vitro transformation model where the presence of the simian virus 40 (SV40) small T (ST) antigen has been shown to be critical for tumorigenic transformation, we investigated whether the ST antigen has a role to play in regulating the energy homeostasis of cancer cells. We find that cells expressing the SV40 ST antigen (+ST cells) are more resistant to glucose deprivation-induced cell death than cells lacking the SV40 ST antigen (-ST cells). Mechanistically, we find that the ST antigen mediates this effect by activating a nutrient-sensing kinase, AMP-activated protein kinase (AMPK). The basal level of active, phosphorylated AMPK was higher in +ST cells than in -ST cells, and these levels increased further in response to glucose deprivation. Additionally, inhibition of AMPK in +ST cells increased the rate of cell death, while activation of AMPK in -ST cells decreased the rate of cell death, under conditions of glucose deprivation. We further show that AMPK mediates its effects, at least in part, by inhibiting mTOR (mammalian target of rapamycin), thereby shutting down protein translation. Finally, we show that +ST cells exhibit a higher percentage of autophagy than -ST cells upon glucose deprivation. Thus, we demonstrate a novel role for the SV40 ST antigen in cancers, where it functions to maintain energy homeostasis during glucose deprivation by activating AMPK, inhibiting mTOR, and inducing autophagy as an alternate energy source.