Huang De, Li Tingting, Wang Lin, Zhang Long, Yan Ronghui, Li Kui, Xing Songge, Wu Gongwei, Hu Lan, Jia Weidong, Lin Sheng-Cai, Dang Chi V, Song Libing, Gao Ping, Zhang Huafeng
CAS Key laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Signaling Network, School of Life Science, Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui 230027, China.
Anhui Key Laboratory of Hepatopancreatobiliary Surgery, Department of General Surgery, Anhui Provincial Hospital, Hefei, Anhui 230001, China.
Cell Res. 2016 Oct;26(10):1112-1130. doi: 10.1038/cr.2016.109. Epub 2016 Sep 20.
Cancer cells are known for their capacity to rewire metabolic pathways to support survival and proliferation under various stress conditions. Ketone bodies, though produced in the liver, are not consumed in normal adult liver cells. We find here that ketone catabolism or ketolysis is re-activated in hepatocellular carcinoma (HCC) cells under nutrition deprivation conditions. Mechanistically, 3-oxoacid CoA-transferase 1 (OXCT1), a rate-limiting ketolytic enzyme whose expression is suppressed in normal adult liver tissues, is re-induced by serum starvation-triggered mTORC2-AKT-SP1 signaling in HCC cells. Moreover, we observe that enhanced ketolysis in HCC is critical for repression of AMPK activation and protects HCC cells from excessive autophagy, thereby enhancing tumor growth. Importantly, analysis of clinical HCC samples reveals that increased OXCT1 expression predicts higher patient mortality. Taken together, we uncover here a novel metabolic adaptation by which nutrition-deprived HCC cells employ ketone bodies for energy supply and cancer progression.
癌细胞以其在各种应激条件下重新连接代谢途径以支持生存和增殖的能力而闻名。酮体虽然在肝脏中产生，但在正常成年肝细胞中并不被消耗。我们在此发现，在营养剥夺条件下，酮体分解代谢或酮解作用在肝细胞癌（HCC）细胞中被重新激活。从机制上讲，3-氧代酸辅酶A转移酶1（OXCT1）是一种限速酮解酶，其表达在正常成年肝脏组织中受到抑制，在HCC细胞中由血清饥饿触发的mTORC2-AKT-SP1信号通路重新诱导。此外，我们观察到HCC中增强的酮解作用对于抑制AMPK激活至关重要，并保护HCC细胞免于过度自噬，从而促进肿瘤生长。重要的是，对临床HCC样本的分析表明，OXCT1表达增加预示着患者更高的死亡率。综上所述，我们在此揭示了一种新的代谢适应机制，即营养剥夺的HCC细胞利用酮体进行能量供应和癌症进展。
