J. Cell Biol.:科学家发现新的癌症治疗靶点

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       癌细胞会增加糖酵解过程从而产生大量能量，该现象称之为Warburg效应。这样才能保证癌细胞在实体瘤中心缺少氧气的位置能够生存。近期发表在The Journal of Cell Biology上的文章表明糖酵解过程异常或与早期癌症发育有关。
3 k, q. Z# l) b1 e多种类型的外界因素都会促使细胞停止分裂，进入一种称之为衰老状态的非活性状态，防止细胞转化为癌细胞。在2005年，Hiroshi Kondoh博士发现在细胞进入衰老状态后会限制糖酵解过程，而增加糖酵解酶PGAM的活性会防止细胞脱离细胞周期。PGAM在多种癌细胞中都有增加，会刺激糖酵解和其他重要环路。但是细胞如何调控PGAM还是未解之谜。( a# R# l/ L; ?, C+ u) ^
Kondoh带领科学家团队基于之前发现继续设计实验，发现在DNA破坏或原癌基因表达的时候PGAM会发生降解，因此在细胞进入衰老阶段时，抑制了糖酵解过程。Mdm2在存在衰老诱导剂的情况下促进PGAM的降解。1 J5 j% C9 \9 ~
Kondoh博士称，显然Mdm2在某些情况下通过降解PGAM来扮演着抑癌因子的角色。近期研究表明PGAM能够作为治疗癌症的靶点。而PGAM的调控因子也会是很好的治疗靶点。* l% L6 Y' a  e: I3 K8 K2 I
     Senescence-inducing stress promotes proteolysis of phosphoglycerate mutase via ubiquitin ligase Mdm2
" w) B8 w! X' i6 RTakumi Mikawa, Takeshi Maruyama, Koji Okamoto, Hitoshi Nakagama, Matilde E. Lleonart, Takeshi Tsusaka, Kousuke Hori, Itsuo Murakami, Taisuke Izumi, Akifumi Takaori-Kondo, Masayuki Yokode, Gordon Peters, David Beach and Hiroshi Kondoh6 Q, u/ t# y6 o- L1 X
Despite the well-documented clinical significance of the Warburg effect, it remains unclear how the aggressive glycolytic rates of tumor cells might contribute to other hallmarks of cancer, such as bypass of senescence. Here, we report that, during oncogene- or DNA damage–induced senescence, Pak1-mediated phosphorylation of phosphoglycerate mutase (PGAM) predisposes the glycolytic enzyme to ubiquitin-mediated degradation. We identify Mdm2 as a direct binding partner and ubiquitin ligase for PGAM in cultured cells and in vitro. Mutations in PGAM and Mdm2 that abrogate ubiquitination of PGAM restored the proliferative potential of primary cells under stress conditions and promoted neoplastic transformation. We propose that Mdm2, a downstream effector of p53, attenuates the Warburg effect via ubiquitination and degradation of PGAM.
3 g7 N- z+ X& x, y: [关键词： 细胞衰老 PGAM Mdm2 糖酵解