Acetylation accumulates PFKFB3 in cytoplasm to promote glycolysis and protects cells from cisplatin-induced apoptosis.
Acetylation accumulates PFKFB3 in cytoplasm to promote glycolysis and protects cells from cisplatin-induced apoptosis.
复制标题
乙酰化使 PFKFB3 在细胞质中积累，促进糖酵解并保护细胞免受顺铂诱导的细胞凋亡
DOI：
10.1038/s41467-018-02950-5
复制
发表时间：
2018-02-06
影响因子：
16.6
通讯作者：
Yuan HX
中科院分区：
文献类型：
--
作者：
Li FL;Liu JP;Bao RX;Yan G;Feng X;Xu YP;Sun YP;Yan W;Ling ZQ;Xiong Y;Guan KL;Yuan HX
摘要癌细胞中糖酵解的增强与保护细胞免受DNA损伤信号的影响有关，尽管其机制在很大程度上尚不清楚。6-磷酸果糖-2-激酶/果糖-2，6-二磷酸酶3（PFKFB 3）催化果糖-2，6-二磷酸的产生，果糖-2，6-二磷酸是糖酵解的有效变构刺激剂。有趣的是，在PFKFB家族的四个成员中，PFKFB 3是唯一定位于细胞核的，尽管原因尚不清楚。在这里，我们表明，化疗药物顺铂促进糖酵解，这是抑制PFKFB 3缺失。从机制上讲，顺铂诱导PFKFB 3在赖氨酸472（K472）处乙酰化，这损害了核定位信号（NLS）的活性并在细胞质中积累PFKFB 3。PFKFB 3的细胞质积累促进其被AMPK磷酸化，导致PFKFB 3活化和糖酵解增强。在异种移植模型中抑制PFKFB 3使肿瘤对顺铂治疗敏感。我们的研究结果揭示了细胞刺激糖酵解以保护DNA免受损伤的机制，并可能提出一种治疗策略，通过靶向PFKFB 3使肿瘤细胞对遗传毒性药物敏感。
AbstractEnhanced glycolysis in cancer cells has been linked to cell protection from DNA damaging signals, although the mechanism is largely unknown. The 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) catalyzes the generation of fructose-2,6-bisphosphate, a potent allosteric stimulator of glycolysis. Intriguingly, among the four members of PFKFB family, PFKFB3 is uniquely localized in the nucleus, although the reason remains unclear. Here we show that chemotherapeutic agent cisplatin promotes glycolysis, which is suppressed byPFKFB3deletion. Mechanistically, cisplatin induces PFKFB3 acetylation at lysine 472 (K472), which impairs activity of the nuclear localization signal (NLS) and accumulates PFKFB3 in the cytoplasm. Cytoplasmic accumulation of PFKFB3 facilitates its phosphorylation by AMPK, leading to PFKFB3 activation and enhanced glycolysis. Inhibition of PFKFB3 sensitizes tumor to cisplatin treatment in a xenograft model. Our findings reveal a mechanism for cells to stimulate glycolysis to protect from DNA damage and potentially suggest a therapeutic strategy to sensitize tumor cells to genotoxic agents by targeting PFKFB3.
登录
查看更多内容
影响因子：
16
作者：
Avalos, JL;Bever, KM;Wolberger, C
通讯作者：
Wolberger, C
影响因子：
64.5
作者：
De Bock, Katrien;Georgiadou, Maria;Carmeliet, Peter
通讯作者：
Carmeliet, Peter
影响因子：
50.3
作者：
Cantelmo AR;Conradi LC;Brajic A;Goveia J;Kalucka J;Pircher A;Chaturvedi P;Hol J;Thienpont B;Teuwen LA;Schoors S;Boeckx B;Vriens J;Kuchnio A;Veys K;Cruys B;Finotto L;Treps L;Stav-Noraas TE;Bifari F;Stapor P;Decimo I;Kampen K;De Bock K;Haraldsen G;Schoonjans L;Rabelink T;Eelen G;Ghesquière B;Rehman J;Lambrechts D;Malik AB;Dewerchin M;Carmeliet P
通讯作者：
Carmeliet P
影响因子：
21.3
作者：
Herrero-Mendez, Angel;Almeida, Angeles;Bolanos, Juan P.
通讯作者：
Bolanos, Juan P.
DOI：
10.1083/jcb.200512059
发表时间：
2006-05-22
期刊：
The Journal of cell biology
影响因子：
--
作者：
Knights CD;Catania J;Di Giovanni S;Muratoglu S;Perez R;Swartzbeck A;Quong AA;Zhang X;Beerman T;Pestell RG;Avantaggiati ML
通讯作者：
Avantaggiati ML