Reduced methylation of PFKFB3 in cancer cells shunts glucose towards the pentose phosphate pathway.
Reduced methylation of PFKFB3 in cancer cells shunts glucose towards the pentose phosphate pathway.
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DOI：
10.1038/ncomms4480
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发表时间：
2014-03-17
影响因子：
16.6
通讯作者：
Suematsu, Makoto
中科院分区：
文献类型：
--
作者：
Yamamoto, Takehiro;Takano, Naoharu;Ishiwata, Kyoko;Ohmura, Mitsuyo;Nagahata, Yoshiko;Matsuura, Tomomi;Kamata, Aki;Sakamoto, Kyoko;Nakanishi, Tsuyoshi;Kubo, Akiko;Hishiki, Takako;Suematsu, Makoto
血红素加氧酶(HO)-1/一氧化碳(CO)保护癌细胞免受氧化应激，但对气体反应的信号机制尚不清楚。在这里，我们使用代谢组学的方法表明，产生2，6-二磷酸果糖(F-2，6-BP)的酶PFKFB3的CO敏感甲基化是激活磷酸果糖激酶-1的开关，磷酸果糖激酶-1是一种限速糖酵解酶。在人类白血病U937细胞中，通过精氨酸甲基转移酶1的修饰，PFKFB3在R131和R134位发生不对称的二甲基化。HO-1诱导或CO导致多种癌细胞中PFKFB3甲基化减少，从而抑制F-2，6-BP，使葡萄糖的利用从糖酵解转向磷酸戊糖途径。PFKFB3甲基化缺失依赖于CO对含血红素的半胱硫氨酸β合成酶的抑制作用。CBS调节再甲基化代谢，增加NADPH以供应还原型谷胱甘肽，保护细胞免受氧化应激和抗癌试剂的影响。一旦PFKFB3的甲基化减少，蛋白质就会经历多泛素化，并在蛋白酶体中降解。这些结果表明，依赖于CO/CBS的PFKFB3甲基化调节决定了定向利用葡萄糖以确保抵抗氧化应激来维持癌细胞的生存。血红素加氧酶1产生一氧化碳，这种副产物已知会改变细胞信号。在这里，作者表明，一氧化碳改变了癌细胞中PFKFB3的甲基化，导致细胞代谢紊乱，并将葡萄糖分流到磷酸戊糖途径。
Haem oxygenase (HO)-1/carbon monoxide (CO) protects cancer cells from oxidative stress, but the gas-responsive signalling mechanisms remain unknown. Here we show using metabolomics that CO-sensitive methylation of PFKFB3, an enzyme producing fructose 2,6-bisphosphate (F-2,6-BP), serves as a switch to activate phosphofructokinase-1, a rate-limiting glycolytic enzyme. In human leukaemia U937 cells, PFKFB3 is asymmetrically di-methylated at R131 and R134 through modification by protein arginine methyltransferase 1. HO-1 induction or CO results in reduced methylation of PFKFB3 in varied cancer cells to suppress F-2,6-BP, shifting glucose utilization from glycolysis toward the pentose phosphate pathway. Loss of PFKFB3 methylation depends on the inhibitory effects of CO on haem-containing cystathionine β-synthase (CBS). CBS modulates remethylation metabolism, and increases NADPH to supply reduced glutathione, protecting cells from oxidative stress and anti-cancer reagents. Once the methylation of PFKFB3 is reduced, the protein undergoes polyubiquitination and is degraded in the proteasome. These results suggest that the CO/CBS-dependent regulation of PFKFB3 methylation determines directional glucose utilization to ensure resistance against oxidative stress for cancer cell survival. Haem oxygenase 1 produces carbon monoxide and this byproduct is known to alter cellular signalling. Here, the authors show that carbon monoxide alters the methylation of PFKFB3 in cancer cells resulting in deregulated cellular metabolism and the shunting of glucose into the pentose phosphate pathway.
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影响因子：
50.3
作者：
Ishimoto, Takatsugu;Nagano, Osamu;Saya, Hideyuki
通讯作者：
Saya, Hideyuki
影响因子：
6.6
作者：
Hattori, Katsuji;Kajimura, Mayumi;Suematsu, Makoto
通讯作者：
Suematsu, Makoto
影响因子：
3.9
作者：
Francoleon, Nestor E.;Carrington, Samantha J.;Fukuto, Jon M.
通讯作者：
Fukuto, Jon M.
影响因子：
21.3
作者：
Herrero-Mendez, Angel;Almeida, Angeles;Bolanos, Juan P.
通讯作者：
Bolanos, Juan P.
影响因子：
64.8
作者：
Frezza, Christian;Zheng, Liang;Gottlieb, Eyal
通讯作者：
Gottlieb, Eyal