Metabolic effect of TAp63α: enhanced glycolysis and pentose phosphate pathway, resulting in increased antioxidant defense.
Metabolic effect of TAp63α: enhanced glycolysis and pentose phosphate pathway, resulting in increased antioxidant defense.
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DOI：
10.18632/oncotarget.2300
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发表时间：
2014-09-15
期刊：
影响因子：
--
通讯作者：
Zolla L
中科院分区：
文献类型：
--
作者：
D'Alessandro A;Amelio I;Berkers CR;Antonov A;Vousden KH;Melino G;Zolla L
TAp 63 α是p53家族的一员，在上皮癌中起着核心作用。最近，p53家族成员在癌症代谢调节中的作用已经出现。为了评估TAp 63 α是否在癌症代谢中发挥作用，我们利用了p53缺失的骨肉瘤Tet-On Saos-2细胞，其中TAp 63 α的表达依赖于培养基中添加强力霉素。通过在13 C-葡萄糖或13 C15 N-谷氨酰胺标记的培养基中孵育细胞进行代谢组学标记实验，以监测诱导表达TAp 63 α后的代谢通量。TAp 63 α的诱导表达导致细胞周期停滞在G1期。从代谢的角度来看，Tap 63 α的表达促进了糖酵解和磷酸戊糖途径，该途径与核苷酸生物合成解偶联，尽管以氧化谷胱甘肽的形式阻止了氧化应激。双13 C-葡萄糖和13 C15 N-谷氨酰胺代谢标记证实，诱导的TAp 63 α表达对应于三羧酸循环中丙酮酸至克雷布斯循环的流量减少和谷氨酰胺用于分解代谢目的的利用减少。关于标记谷氨酰胺的合成代谢利用，结果并不确定，因为尚不清楚在棕榈酸酯中观察到的谷氨酰胺衍生标记的轻微TAp 63 α依赖性增加在多大程度上与还原羧化速率增加和脂肪酸从头合成有关。最后，生物信息学的阐述强调了患者生存率与p63和戊糖磷酸途径的限速酶G6 PD和PGD的共表达之间的联系。
TAp63α is a member of the p53 family, which plays a central role in epithelial cancers. Recently, a role has emerged for p53 family members in cancer metabolic modulation. In order to assess whether TAp63α plays a role in cancer metabolism, we exploited p53-null osteosarcoma Tet-On Saos-2 cells, in which the expression of TAp63α was dependent on doxycycline supplementation to the medium. Metabolomics labeling experiments were performed by incubating the cells in 13C-glucose or 13C15N-glutamine-labeled culture media, as to monitor metabolic fluxes upon induced expression of TAp63α. Induced expression of TAp63α resulted in cell cycle arrest at the G1 phase. From a metabolic standpoint, expression of Tap63α promoted glycolysis and the pentose phosphate pathway, which was uncoupled from nucleotide biosynthesis, albeit prevented oxidative stress in the form of oxidized glutathione. Double 13C-glucose and 13C15N-glutamine metabolic labeling confirmed that induced expression of TAp63α corresponded to a decreased flux of pyruvate to the Krebs cycle and decreased utilization of glutamine for catabolic purposes in the TCA cycle. Results were not conclusive in relation to anabolic utilization of labeled glutamine, since it is unclear to what extent the observed minor TAp63α-dependent increases of glutamine-derived labeling in palmitate could be tied to increased rates of reductive carboxylation and de novo synthesis of fatty acids. Finally, bioinformatics elaborations highlighted a link between patient survival rates and the co-expression of p63 and rate limiting enzymes of the pentose phosphate pathway, G6PD and PGD.
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影响因子：
2.2
作者：
Heikal AA
通讯作者：
Heikal AA
影响因子：
11.4
作者：
Bensaad, Karim;Cheung, Eric C.;Vousden, Karen H.
通讯作者：
Vousden, Karen H.
影响因子：
4.4
作者：
D'Alessandro, Angelo;Marrocco, Cristina;Zolla, Lello
通讯作者：
Zolla, Lello
影响因子：
64.8
作者：
Curtis, Christina;Shah, Sohrab P.;Chin, Suet-Feung;Turashvili, Gulisa;Rueda, Oscar M.;Dunning, Mark J.;Speed, Doug;Lynch, Andy G.;Samarajiwa, Shamith;Yuan, Yinyin;Graef, Stefan;Ha, Gavin;Haffari, Gholamreza;Bashashati, Ali;Russell, Roslin;McKinney, Steven;Langerod, Anita;Green, Andrew;Provenzano, Elena;Wishart, Gordon;Pinder, Sarah;Watson, Peter;Markowetz, Florian;Murphy, Leigh;Ellis, Ian;Purushotham, Arnie;Borresen-Dale, Anne-Lise;Brenton, James D.;Tavare, Simon;Caldas, Carlos;Aparicio, Samuel
通讯作者：
Aparicio, Samuel
影响因子：
4.3
作者：
Giacobbe, Arianna;Bongiorno-Borbone, Lucilla;Peschiaroli, Angelo
通讯作者：
Peschiaroli, Angelo