Dysregulation of the mevalonate pathway promotes transformation
Dysregulation of the mevalonate pathway promotes transformation
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DOI：
10.1073/pnas.0910258107
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发表时间：
2010-08-24
影响因子：
11.1
通讯作者：
Penn, Linda Z.
中科院分区：
文献类型：
--
作者：
Clendening, James W.;Pandyra, Aleks;Penn, Linda Z.
多年来，人们一直认识到癌症代谢的重要性，但代谢途径如何与致癌信号相互联系的复杂性尚未完全了解。通过清楚地了解新陈代谢如何促进肿瘤发生，我们将能够更好地将这些基本生化途径的靶向整合到患者护理中。甲羟戊酸 (MVA) 途径由其限速酶羟甲基戊二酰辅酶 A 还原酶 (HMGCR) 调节，是产生包括胆固醇和类异戊二烯在内的多种基本终产物所必需的。尽管从心血管疾病的角度进行了多年的广泛研究，但 MVA 通路失调对人类癌症的影响仍然很大程度上尚未被探索。我们通过证明通过全长 HMGCR 或其新剪接变体的异位表达实现的 MVA 途径失调促进转化，从而直接解决这个问题。异位 HMGCR 会在不依赖锚定的条件下促进转化细胞和非转化细胞的生长，或作为免疫功能低下小鼠的异种移植物，并且重要的是，与 RAS 合作驱动原代小鼠胚胎成纤维细胞的转化。我们进一步探讨了 MVA 通路是否可能在人类癌症的病因学中发挥作用，并在对原发性乳腺癌的六个微阵列数据集的荟萃分析中表明，HMGCR 和其他 MVA 通路基因的高 mRNA 水平与不良预后相关。综上所述，我们的结果表明 HMGCR 是一种候选代谢癌基因，并为进一步探索 HMGCR 抑制剂的他汀类药物家族作为抗癌药物提供了分子原理。
The importance of cancer metabolism has been appreciated for many years, but the intricacies of how metabolic pathways inter-connect with oncogenic signaling are not fully understood. With a clear understanding of how metabolism contributes to tumorigenesis, we will be better able to integrate the targeting of these fundamental biochemical pathways into patient care. The mevalonate (MVA) pathway, paced by its rate-limiting enzyme, hydroxymethylglutaryl coenzyme A reductase (HMGCR), is required for the generation of several fundamental end-products including cholesterol and isoprenoids. Despite years of extensive research from the perspective of cardiovascular disease, the contribution of a dysregulated MVA pathway to human cancer remains largely unexplored. We address this issue directly by showing that dysregulation of the MVA pathway, achieved by ectopic expression of either full-length HMGCR or its novel splice variant, promotes transformation. Ectopic HMGCR accentuates growth of transformed and nontransformed cells under anchorage-independent conditions or as xenografts in immunocompromised mice and, importantly, cooperates with RAS to drive the transformation of primary mouse embryonic fibroblasts cells. We further explore whether the MVA pathway may play a role in the etiology of human cancers and show that high mRNA levels of HMGCR and additional MVA pathway genes correlate with poor prognosis in a meta-analysis of six microarray datasets of primary breast cancer. Taken together, our results suggest that HMGCR is a candidate metabolic oncogene and provide a molecular rationale for further exploring the statin family of HMGCR inhibitors as anticancer agents.