Paraoxonase 2 Facilitates Pancreatic Cancer Growth and Metastasis by Stimulating GLUT1-Mediated Glucose Transport.
Paraoxonase 2 Facilitates Pancreatic Cancer Growth and Metastasis by Stimulating GLUT1-Mediated Glucose Transport.
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二氧氧蛋白酶2通过刺激GLUT1介导的葡萄糖转运来促进胰腺癌的生长和转移。
DOI：
10.1016/j.molcel.2017.07.014
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发表时间：
2017-08-17
期刊：
影响因子：
16
通讯作者：
Wajapeyee N
中科院分区：
文献类型：
--
作者：
Nagarajan A;Dogra SK;Sun L;Gandotra N;Ho T;Cai G;Cline G;Kumar P;Cowles RA;Wajapeyee N
代谢失调是人类癌症的标志，并且糖酵解和谷氨酰胺代谢途径显示在胰腺导管腺癌（PDAC）中失调。为了鉴定PDAC肿瘤生长和转移的新代谢调节因子，我们使用短发夹RNA系统地敲除在人PDAC肿瘤样品中过表达的代谢基因。我们发现p53在转录上抑制对氧磷酶2（PON 2），PON 2通过气孔蛋白调节GLUT 1介导的葡萄糖转运。PON 2的缺失启动细胞饥饿反应并激活AMP活化蛋白激酶（AMPK）。反过来，AMPK激活FOXO 3A及其转录靶点，FOXO 3A诱导失巢凋亡抑制PDAC肿瘤生长和转移。AMPK的药理学或遗传学激活，类似于PON 2抑制，阻断PDAC肿瘤生长。总的来说，我们的研究结果确定PON 2作为一种新的葡萄糖转运调节剂，调节PDAC肿瘤生长和转移所必需的易处理的途径。纳加拉詹等人，显示PON 2在胰腺癌中过表达，并且是胰腺癌生长和转移所必需的。PON 2增加葡萄糖摄取以保护胰腺癌细胞免受肿瘤诱导的细胞死亡，这部分通过抑制AMPK→ FOXO 3A → GST-A信号通路发生。
Metabolic deregulation is a hallmark of human cancers, and the glycolytic and glutamine metabolism pathways were shown to be deregulated in pancreatic ductal adenocarcinoma (PDAC). To identify new metabolic regulators of PDAC tumor growth and metastasis, we systematically knocked down metabolic genes that were overexpressed in human PDAC tumor samples using short hairpin RNAs. We found that p53 transcriptionally represses paraoxonase 2 (PON2), which regulates GLUT1-mediated glucose transport via stomatin. The loss of PON2 initiates the cellular starvation response and activates AMP-activated protein kinase (AMPK). In turn, AMPK activates FOXO3A and its transcriptional target, PUMA, which induces anoikis to suppress PDAC tumor growth and metastasis. Pharmacological or genetic activation of AMPK, similar to PON2 inhibition, blocks PDAC tumor growth. Collectively, our results identify PON2 as a new modulator of glucose transport that regulates a pharmacologically tractable pathway necessary for PDAC tumor growth and metastasis. Nagarajan et al., shows that PON2 is overexpressed in pancreatic cancer and is necessary for pancreatic cancer growth and metastasis. PON2 increases glucose uptake to protect pancreatic cancer cells from detachment-induced cell death, which in part occurs through suppression of AMPK→FOXO3A→PUMA signaling pathway.
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癌细胞对葡萄糖限制和双胍类药物敏感性的代谢决定因素。
影响因子：
64.8
作者：
Birsoy, Kivanc;Possemato, Richard;Lorbeer, Franziska K.;Bayraktar, Erol C.;Thiru, Prathapan;Yucel, Burcu;Wang, Tim;Chen, Walter W.;Clish, Clary B.;Sabatini, David M.
通讯作者：
Sabatini, David M.
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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
癌代谢中的葡萄糖转运蛋白。
影响因子：
3.4
作者：
Adekola K;Rosen ST;Shanmugam M
通讯作者：
Shanmugam M
影响因子：
28.2
作者：
Cantor JR;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
64.8
作者：
Chelur, DS;Ernstrom, GG;Chalfie, M
通讯作者：
Chalfie, M