Fatty acid synthase: A metabolic oncogene in prostate cancer?
Fatty acid synthase: A metabolic oncogene in prostate cancer?
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DOI：
10.1002/jcb.10708
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发表时间：
2004-01-01
影响因子：
4
通讯作者：
Loda, M
中科院分区：
文献类型：
--
作者：
Baron, A;Migita, T;Loda, M
1920年，Warburg提出，即使在氧气充足的情况下，肿瘤也始终依赖无氧途径将葡萄糖转化为ATP[Warberg，1956]，尽管它的能量供应效率低于有氧糖酵解。造成这种情况的原因至今仍不清楚。通常，实体肿瘤的微环境包含低氧和高酸度区域。在这种情况下，缺氧可以以表观遗传的方式发挥作用，诱导基因表达和新陈代谢的变化以求生存。可以合理地假设，只有能够对限制氧气供应和过度产生乳酸引起的酸中毒产生不寻常耐受性的肿瘤细胞才能存活。除了葡萄糖代谢发生的显著变化外，对人类癌症患者的研究表明，游离脂肪酸的周转、氧化和清除通常也会增加[Legaspi等人，1987；Hyltander等人，1991]。例如，肿瘤细胞产生的一种脂肪动员因子似乎是全身脂肪酸氧化增加的原因[Russell和Tisdale，2002]。正如半个多世纪前首次证明的那样，肿瘤组织中的脂肪酸合成速度也非常快[Medes et al.，1953]。重要的是，C-14葡萄糖研究表明，在肿瘤细胞中，尽管有足够的营养供应，但几乎所有的脂肪酸都来自从头合成[Sabine和Abraham，1967；Ookhten等人，1984；Weiss等人，1986]。此外，与Fas水平正常的肿瘤相比，过度表达脂肪酸合成酶(Fas)的肿瘤表现出侵袭性的生物学行为，这表明Fas过表达赋予了选择性生长优势。在这里，我们将回顾Fas在细胞凋亡和增殖等重要细胞过程中所起的作用。此外，还将探讨Fas在前列腺癌细胞代谢途径改变中可能扮演的角色。由于前列腺癌这种酶的频繁过度表达，Fas构成了这种疾病的治疗靶点。(C)2003年Wiley-Liss，Inc.
In 1920, Warburg suggested that tumors consistently rely on anaerobic pathways to convert glucose to ATP even in the presence of abundant oxygen [Warberg, 1956] despite the fact that it is less efficient for energy supply than aerobic glycolysis. The reasons for this remain obscure to date. More often than not, the microenvironment of solid tumors contains regions of poor oxygenation and high acidity. In this context hypoxia can act in an epigenetic fashion, inducing changes in gene expression and in metabolism for survival. It is reasonable to assume that only the tumor cells capable of developing an unusual tolerance to limiting oxygen availability and to the acidosis resulting from excessive lactate production, can survive. In addition to the striking changes that occur in glucose metabolism, studies in human cancer patients suggest that there is often also an increase in free fatty acid turnover, oxidation and clearance [Legaspi et al., 1987; Hyltander et al., 1991]. For instance, a lipid mobilizing factor produced by tumor cells appears to be responsible for the increase in whole body fatty acid oxidation [Russell and Tisdale, 2002]. Fatty acids synthesis in tumor tissues also occurs at very high rates, as first demonstrated more than half a century ago [Medes et al., 1953]. Importantly, C-14 glucose studies have shown that in tumor cells almost all fatty acids derive from de novo synthesis despite adequate nutritional supply [Sabine and Abraham, 1967; Ookhtens et al., 1984; Weiss et al., 1986]. In addition, tumors overexpressing fatty acid synthase (FAS), the enzyme responsible for de novo synthesis of fatty acids, display aggressive biologic behavior compared to those tumors with normal FAS levels, suggesting that FAS overexpression confers a selective growth advantage. Here, we will review the roles that FAS plays in important cellular processes such as apoptosis and proliferation. In addition, speculations on the putative role of FAS in the altered metabolic pathways of prostate cancer cells will be explored. Because of the frequent overexpression of this enzyme prostate cancer, FAS constitutes a therapeutic target in this disease. (C) 2003 Wiley-Liss, Inc.