Rab25 increases cellular ATP and glycogen stores protecting cancer cells from bioenergetic stress.
Rab25 increases cellular ATP and glycogen stores protecting cancer cells from bioenergetic stress.
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DOI：
10.1002/emmm.201100193
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发表时间：
2012-02
影响因子：
11.1
通讯作者：
Mills, Gordon B.
中科院分区：
文献类型：
--
作者：
Cheng, Kwai Wa;Agarwal, Roshan;Mitra, Shreya;Lee, Ju-Seog;Carey, Mark;Gray, Joe W.;Mills, Gordon B.
由于肿瘤血管有限以及由此产生的营养、生长因子和缺氧可导致细胞死亡和抑制肿瘤生长，癌细胞在肿瘤进展过程中受到新陈代谢的压力。我们证明了Rab25，一个参与内体循环的小GTP酶，在多个肿瘤谱系中被基因组扩增，是细胞生物能量学和自噬的关键调节因子。RAB25通过结合和激活AKT来防止细胞凋亡和自噬，从而增加葡萄糖摄取，改善细胞生物能量，从而提高营养胁迫期间的存活率。出乎意料的是，Rab25诱导了上皮性癌细胞中糖原的积累，这是一个以前没有发现的过程。值得注意的是，基础ATP水平的增加与AKT依赖的葡萄糖摄取和糖原储存的增加相结合，使得在生物能量应激期间维持ATP水平。这些发现的临床相关性被丰富的生物能量学靶点的Rab25依赖的表达谱识别预后不良的患者的能力所验证。因此，Rab25是细胞生物能量学的一个意想不到的调节者，被认为是一个有用的生物标记物和潜在的治疗靶点。
Cancer cells are metabolically stressed during tumour progression due to limited tumour vascularity and resultant nutrient, growth factor and oxygen deficiency that can induce cell death and inhibit tumour growth. We demonstrate that Rab25, a small GTPase involved in endosomal recycling, that is genomically amplified in multiple tumour lineages, is a key regulator of cellular bioenergetics and autophagy. RAB25 enhanced survival during nutrient stress by preventing apoptosis and autophagy via binding and activating AKT leading to increased glucose uptake and improved cellular bioenergetics. Unexpectedly, Rab25 induced the accumulation of glycogen in epithelial cancer cells, a process not previously identified. Strikingly, an increase in basal ATP levels combined with AKT-dependent increases in glucose uptake and glycogen storage allowed maintenance of ATP levels during bioenergetic stress. The clinical relevance of these findings was validated by the ability of a Rab25-dependent expression profile enriched for bioenergetics targets to identify patients with a poor prognosis. Thus, Rab25 is an unexpected regulator of cellular bioenergetics implicated as a useful biomarker and potential therapeutic target.
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