AMPK-mediated energy homeostasis and associated metabolic effects on cancer cell response and resistance to cetuximab.
AMPK-mediated energy homeostasis and associated metabolic effects on cancer cell response and resistance to cetuximab.
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DOI：
10.18632/oncotarget.3432
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发表时间：
2015-05-10
期刊：
影响因子：
--
通讯作者：
Fan Z
中科院分区：
文献类型：
--
作者：
Li X;Lu Y;Lu H;Luo J;Hong Y;Fan Z
我们之前报道过西妥昔单抗，一种egfr阻断抗体，通过下调HIF-1α抑制癌症代谢，并逆转癌细胞中的Warburg效应。在这里，我们报道西妥昔单抗抑制HIF-1转录活性并不一定导致成功抑制细胞增殖。在一些头颈部鳞状细胞癌（HNSCC）细胞系中，我们观察到西妥昔单抗治疗后细胞内ATP水平振荡下降和增加的模式，其幅度和动力学因细胞系而异，似乎与细胞对西妥昔单抗的反应程度有关。在AMPK活性基础水平较低且对西妥昔单抗诱导的生长抑制有反应的HNSCC细胞中，AMPK存在短暂的、依赖于lkb1的激活。相比之下，具有高基础水平AMPK活性的HNSCC细胞对西妥昔单抗诱导的生长抑制不太敏感，尽管西妥昔单抗有效抑制EGFR下游信号传导。敲低或抑制AMPK可通过诱导细胞凋亡显著增强对西妥昔单抗的应答。这些发现表明，AMPK的短暂激活是细胞对西妥昔单抗反应的早期代谢标志，而AMPK的高和持续活性是癌细胞在西妥昔单抗治疗中存活的重要机制。
We previously reported that cetuximab, an EGFR-blocking antibody, inhibits cancer metabolism via downregulation of HIF-1α and reverses the Warburg effect in cancer cells. Here, we report that inhibition of HIF-1 transcriptional activity by cetuximab does not necessarily lead to successful inhibition of cell proliferation. In several head and neck squamous cell carcinoma (HNSCC) cell lines, we observed a pattern of oscillating decrease and increase of intracellular ATP level after cetuximab treatment, and the magnitude and kinetics of which varied by cell line and appeared to be linked to the extent of cellular response to cetuximab. In HNSCC cells with low basal level of AMPK activity and that responded to cetuximab-induced growth inhibition, there was a transient, LKB1-dependent activation of AMPK. In contrast, HNSCC cells that had a high basal level of AMPK activity were less sensitive to cetuximab-induced growth inhibition despite effective inhibition of EGFR downstream signaling by cetuximab. Knockdown or inhibition of AMPK markedly enhanced response to cetuximab via induction of apoptosis. These findings indicate that a transient activation of AMPK is an early metabolic marker of cellular response to cetuximab and that high and sustained AMPK activity is an important mechanism by which cancer cells survive cetuximab treatment.
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AMP激活的蛋白激酶对ULK1（HATG1）的磷酸化将能量传感连接到线粒体。
DOI：
10.1126/science.1196371
发表时间：
2011-01-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Egan DF;Shackelford DB;Mihaylova MM;Gelino S;Kohnz RA;Mair W;Vasquez DS;Joshi A;Gwinn DM;Taylor R;Asara JM;Fitzpatrick J;Dillin A;Viollet B;Kundu M;Hansen M;Shaw RJ
通讯作者：
Shaw RJ
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
9.7
作者：
Lu, Haiquan;Liang, Ke;Lu, Yang;Fan, Zhen
通讯作者：
Fan, Zhen
影响因子：
3.5
作者：
CARLING, D;ZAMMIT, VA;HARDIE, DG
通讯作者：
HARDIE, DG
影响因子：
45.3
作者：
Khambata-Ford, Shirin;Garrett, Christopher R.;Mauro, David J.
通讯作者：
Mauro, David J.