Cancer's sweet tooth: the Janus effect of glucose metabolism in tumorigenesis
Cancer's sweet tooth: the Janus effect of glucose metabolism in tumorigenesis
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DOI：
10.1016/s0140-6736(06)68228-7
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发表时间：
2006-02-18
期刊：
影响因子：
168.9
通讯作者：
Ashrafian, H
中科院分区：
文献类型：
--
作者：
Ashrafian, H
尽管奥托·沃伯格因肯定新陈代谢在癌症发生中的作用而获得1931年诺贝尔奖，但人们对新陈代谢和癌症之间的这种联系几乎没有进一步的兴趣。不感兴趣在一定程度上归因于这样一种观点，即沃伯格对癌症发生过程中糖酵解转变之间的关系的描述可能是一种附带现象，而不是一种机械决定因素。通过研究关键的细胞能量传感器AMP激活的蛋白激酶(AMPK)，我假设中间代谢和肿瘤之间的联系随着时间的推移而变化。通过碳水化合物的积累和AMPK的泛抑制，癌前肿瘤可能通过抑制衰老而获得复制优势。相反，肿瘤抑制因子有缺陷的恶性肿瘤会经历“糖酵解开关”，部分是通过耐受一定程度的AMPK活性来减轻底物的限制。我认为，这种与中间代谢的Janus面孔关系有助于癌症的发生；如果得到证实，这一发现将对公众健康产生重要影响，因为它将支持预防肥胖、限制卡路里和锻炼可以降低癌症易感性的观点。
Despite Otto Warburg's 1931 Nobel Prize for his work affirming the role of metabolism in carcinogenesis, there has been little further interest in this association between metabolism and cancer. Disinterest has, in part, been attributable to the notion that Warburg's description of a relation between a shift to glycolysis in carcinogenesis may be an epiphenomenon rather than a mechanistic determinant. By studying the critical cellular energy sensor AMP-activated protein kinase (AMPK), I postulate that the association between intermediary metabolism and tumours varies over time. Through accumulation of carbohydrates and pan-inhibition of AMPK, premalignant tumours may gain a replicative advantage through the repression of senescence. Conversely, malignant tumours, with a defective tumour suppressor contingent, undergo a "glycolytic switch", in part by tolerating a degree of AMPK activation, to mitigate substrate limitation. I contend that this Janus-faced relation with intermediary metabolism contributes to carcinogenesis; if proven, this finding would have important implications for public health, in that it would lend support to the idea that prevention of obesity, and caloric restriction and exercise could reduce the predisposition to cancer.