PIK3CA mutant tumors depend on oxoglutarate dehydrogenase
PIK3CA mutant tumors depend on oxoglutarate dehydrogenase
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DOI：
10.1073/pnas.1617922114
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发表时间：
2017-04-25
影响因子：
11.1
通讯作者：
Hahn, William C.
中科院分区：
文献类型：
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作者：
Ilic, Nina;Birsoy, Kivanc;Hahn, William C.
在相当一部分人类癌症中发现了致癌的PIK3CA突变，但在临床试验中，对PI3K的治疗抑制只显示出有限的成功。为了了解突变的PIK3CA如何促进癌细胞的增殖，我们在大量具有基因组注释的癌细胞系中进行了基因组规模的功能丧失筛选。不出所料，我们发现PIK3CA突变的癌细胞需要PIK3CA，但也需要TCA循环酶2-氧代戊二酸脱氢酶(OGDH)的表达。为了了解致癌基因PIK3CA和OGDH功能之间的关系，我们询问了代谢需求，发现对葡萄糖代谢的依赖增加了对PIK3CA突变细胞增殖的依赖。功能代谢研究表明，抑制OGDH会增加代谢物2-氧戊二酸(2OG)的水平。我们发现，这种2OG水平的增加，无论是通过OGDH抑制还是外源2OG处理，都会导致天冬氨酸耗竭，这在PIK3CA突变细胞中特异性地表现为营养不良。天冬氨酸水平的降低解除了苹果酸-天冬氨酸穿梭的调节，这对细胞质NAD(+)的再生非常重要，NAD(+)通过糖酵解维持快速的葡萄糖分解。因此，由于PIK3CA突变细胞表现出对葡萄糖代谢的严重依赖，苹果酸-天冬氨酸穿梭调控的解除导致了由于无法维持NAD(+)/NADH动态平衡而导致的特定的增殖障碍。这些观察结果共同定义了一种由反复突变的癌基因造成的精确的代谢脆弱性。
Oncogenic PIK3CA mutations are found in a significant fraction of human cancers, but therapeutic inhibition of PI3K has only shown limited success in clinical trials. To understand how mutant PIK3CA contributes to cancer cell proliferation, we used genome scale loss-of-function screening in a large number of genomically annotated cancer cell lines. As expected, we found that PIK3CA mutant cancer cells require PIK3CA but also require the expression of the TCA cycle enzyme 2-oxoglutarate dehydrogenase (OGDH). To understand the relationship between oncogenic PIK3CA and OGDH function, we interrogated metabolic requirements and found an increased reliance on glucose metabolism to sustain PIK3CA mutant cell proliferation. Functional metabolic studies revealed that OGDH suppression increased levels of the metabolite 2-oxoglutarate (2OG). We found that this increase in 2OG levels, either by OGDH suppression or exogenous 2OG treatment, resulted in aspartate depletion that was specifically manifested as auxotrophy within PIK3CA mutant cells. Reduced levels of aspartate deregulated the malate-aspartate shuttle, which is important for cytoplasmic NAD(+) regeneration that sustains rapid glucose breakdown through glycolysis. Consequently, because PIK3CA mutant cells exhibit a profound reliance on glucose metabolism, malate-aspartate shuttle deregulation leads to a specific proliferative block due to the inability to maintain NAD(+)/NADH homeostasis. Together these observations define a precise metabolic vulnerability imposed by a recurrently mutated oncogene.