Chen Guo-Qing, Gong Rui-Hong, Yang Da-Jian, Zhang Ge, Lu Ai-Ping, Yan Siu-Cheong, Lin Shu-Hai, Bian Zhao-Xiang
Laboratory of Brain and Gut Research, Center for Clinical Research on Chinese Medicine, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.
Chongqing Academy of Chinese Materia Medica, Chongqing, China.
Cell Death Dis. 2017 May 11;8(5):e2789. doi: 10.1038/cddis.2017.203.
Autophagy has a key role in metabolism and impacts on tumorigenesis. Our previous study found that halofuginone (HF) exerts anticancer activity in colorectal cancer (CRC) by downregulating Akt/mTORC1 (mechanistic target of rapamycin complex 1) signaling pathway. But whether and how HF regulates autophagy and metabolism to inhibit cancer growth remains an open question. Here, we unveil that HF activates ULK1 by downregulation of its phosphorylation site at Ser757 through Akt/mTORC1 signaling pathway, resulting in induction of autophagic flux under nutrient-rich condition. On the other hand, HF inactivates ULK1 by downregulation of its phosphorylation sites at Ser317 and Ser777 through LKB1/AMPK signaling pathway, resulting in autophagic inhibition under nutrient-poor condition. Furthermore, Atg7-dependent autophagosome formation is also induced under nutrient-rich condition or blocked in nutrient-poor environment, respectively, upon HF treatment. More interestingly, we also found that HF inhibits glycolysis under nutrient-rich condition, whereas inhibits gluconeogenesis under nutrient-poor condition in an Atg7-dependent manner, suggesting that autophagy has a pivotal role of glucose metabolism upon HF treatment. Subsequent studies showed that HF treatment retarded tumor growth in xenograft mice fed with either standard chow diet or caloric restriction through dual regulation of autophagy in vivo. Together, HF has a dual role in autophagic modulation depending on nutritional conditions for anti-CRC.
自噬在新陈代谢中起关键作用，并影响肿瘤发生。我们之前的研究发现，常山酮（HF）通过下调Akt/mTORC1（雷帕霉素机制性靶蛋白复合物1）信号通路在结直肠癌（CRC）中发挥抗癌活性。但HF是否以及如何调节自噬和新陈代谢以抑制癌症生长仍是一个悬而未决的问题。在此，我们揭示HF通过Akt/mTORC1信号通路下调ULK1在Ser757处的磷酸化位点来激活ULK1，从而在营养丰富的条件下诱导自噬流。另一方面，HF通过LKB1/AMPK信号通路下调ULK1在Ser317和Ser777处的磷酸化位点来使ULK1失活，从而在营养匮乏的条件下抑制自噬。此外，经HF处理后，在营养丰富的条件下Atg7依赖的自噬体形成也被诱导，而在营养匮乏的环境中则被阻断。更有趣的是，我们还发现HF在营养丰富的条件下抑制糖酵解，而在营养匮乏的条件下以Atg7依赖的方式抑制糖异生，这表明自噬在HF处理时对葡萄糖代谢起关键作用。随后的研究表明，HF处理通过体内自噬的双重调节延缓了喂食标准饲料或热量限制的异种移植小鼠的肿瘤生长。总之，HF在自噬调节中具有双重作用，这取决于营养状况对CRC的影响。
