Lipophagy-mediated cholesterol synthesis inhibition is required for the survival of hepatocellular carcinoma under glutamine deprivation.
Lipophagy-mediated cholesterol synthesis inhibition is required for the survival of hepatocellular carcinoma under glutamine deprivation.
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DOI：
10.1016/j.redox.2023.102732
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发表时间：
2023-07
期刊：
影响因子：
11.4
通讯作者：
Yue, Xuetian
中科院分区：
文献类型：
--
作者：
Kong, Youzi;Wu, Mengting;Wan, Xiaoyu;Sun, Min;Zhang, Yankun;Wu, Zhuanchang;Li, Chunyang;Liang, Xiaohong;Gao, Lifen;Ma, Chunhong;Yue, Xuetian
谷氨酰胺对肿瘤进展至关重要，限制其可用性正成为一种潜在的治疗策略。肿瘤细胞的代谢可塑性有助于它们适应谷氨酰胺限制。然而，胆固醇代谢在这一过程中的作用相对未被探索。在这里，我们报道了谷氨酰胺剥夺抑制肝细胞癌（HCC）中胆固醇的合成。胆固醇合成的重新激活增强了谷氨酰胺剥夺诱导的肝癌细胞死亡，这部分是由于NADPH耗竭和脂质过氧化作用的增强。从机制上讲，谷氨酰胺剥夺诱导脂肪吞噬将胆固醇从脂滴（LD）转运到内质网（ER），从而抑制SREBF 2成熟和胆固醇合成，并维持氧化还原平衡以维持生存。谷氨酰胺剥夺降低mTORC 1活性，诱导脂肪吞噬。重要的是，施用U18666A、CQ或shTSC2病毒进一步增强了GPNA诱导的异种移植肿瘤生长抑制。临床数据支持谷氨酰胺利用与胆固醇合成正相关，这与HCC患者的不良预后有关。总的来说，我们的研究表明，胆固醇合成抑制是必需的肝癌生存谷氨酰胺限制的肿瘤微环境。
Glutamine is critical for tumor progression, and restriction of its availability is emerging as a potential therapeutic strategy. The metabolic plasticity of tumor cells helps them adapting to glutamine restriction. However, the role of cholesterol metabolism in this process is relatively unexplored. Here, we reported that glutamine deprivation inhibited cholesterol synthesis in hepatocellular carcinoma (HCC). Reactivation of cholesterol synthesis enhanced glutamine-deprivation-induced cell death of HCC cells, which is partially duo to augmented NADPH depletion and lipid peroxidation. Mechanistically, glutamine deprivation induced lipophagy to transport cholesterol from lipid droplets (LDs) to endoplasmic reticulum (ER), leading to inhibit SREBF2 maturation and cholesterol synthesis, and maintain redox balance for survival. Glutamine deprivation decreased mTORC1 activity to induce lipophagy. Importantly, administration of U18666A, CQ, or shTSC2 viruses further augmented GPNA-induced inhibition of xenograft tumor growth. Clinical data supported that glutamine utilization positively correlated with cholesterol synthesis, which is associated with poor prognosis of HCC patients. Collectively, our study revealed that cholesterol synthesis inhibition is required for the survival of HCC under glutamine-restricted tumor microenvironment.
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DOI：
10.1083/jcb.201403009
发表时间：
2014-07-21
期刊：
The Journal of cell biology
影响因子：
--
作者：
Chen R;Zou Y;Mao D;Sun D;Gao G;Shi J;Liu X;Zhu C;Yang M;Ye W;Hao Q;Li R;Yu L
通讯作者：
Yu L
DOI：
10.1016/j.bbrc.2018.05.122
发表时间：
2018-07-07
影响因子：
3.1
作者：
Liu, Zheng;Liu, Xiaowen;Cao, Qingwei
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Cao, Qingwei
影响因子：
64.5
作者：
Moon, Sung-Hwan;Huang, Chun-Hao;Prives, Carol
通讯作者：
Prives, Carol
通过自噬调节脂质液滴。
影响因子：
10.9
作者：
Dong, Hanqing;Czaja, Mark J.
通讯作者：
Czaja, Mark J.
影响因子：
11.2
作者：
Kamphorst JJ;Nofal M;Commisso C;Hackett SR;Lu W;Grabocka E;Vander Heiden MG;Miller G;Drebin JA;Bar-Sagi D;Thompson CB;Rabinowitz JD
通讯作者：
Rabinowitz JD