Dysregulated cholesterol homeostasis results in resistance to ferroptosis increasing tumorigenicity and metastasis in cancer.
Dysregulated cholesterol homeostasis results in resistance to ferroptosis increasing tumorigenicity and metastasis in cancer.
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DOI：
10.1038/s41467-021-25354-4
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发表时间：
2021-08-24
影响因子：
16.6
通讯作者：
McDonnell DP
中科院分区：
文献类型：
--
作者：
Liu W;Chakraborty B;Safi R;Kazmin D;Chang CY;McDonnell DP
高胆固醇血症和血脂异常与许多癌症类型的风险增加以及已确诊疾病患者的不良结局相关。尽管发生这种情况的机制是多因素的，但我们确定细胞长期暴露于27-羟基胆固醇（27 HC）（一种丰富的循环胆固醇代谢物），选择表现出细胞摄取和/或脂质生物合成增加的细胞。这些细胞表现出显著增加的致瘤和转移能力。值得注意的是，累积的脂质对细胞施加的代谢应激需要GPX 4的持续表达，GPX 4是铁凋亡细胞死亡的负调节因子。我们表明，铁凋亡的抗性是转移性细胞的一个特征，并进一步证明GPX 4敲低减弱了27 HC抗性细胞的增强的致瘤性和转移性活性。这些发现突出了铁凋亡在肿瘤生长和转移中的普遍重要性，并表明血脂异常/高胆固醇血症通过选择对铁凋亡细胞死亡具有抗性的细胞来影响癌症发病机制。高胆固醇与癌症风险增加有关，但其潜在机制尚未完全了解。在这里，作者表明胆固醇代谢物诱导代谢重编程，产生耐铁蛋白分解的癌细胞，导致肿瘤生长和转移增加。
Hypercholesterolemia and dyslipidemia are associated with an increased risk for many cancer types and with poor outcomes in patients with established disease. Whereas the mechanisms by which this occurs are multifactorial we determine that chronic exposure of cells to 27-hydroxycholesterol (27HC), an abundant circulating cholesterol metabolite, selects for cells that exhibit increased cellular uptake and/or lipid biosynthesis. These cells exhibit substantially increased tumorigenic and metastatic capacity. Notably, the metabolic stress imposed upon cells by the accumulated lipids requires sustained expression of GPX4, a negative regulator of ferroptotic cell death. We show that resistance to ferroptosis is a feature of metastatic cells and further demonstrate that GPX4 knockdown attenuates the enhanced tumorigenic and metastatic activity of 27HC resistant cells. These findings highlight the general importance of ferroptosis in tumor growth and metastasis and suggest that dyslipidemia/hypercholesterolemia impacts cancer pathogenesis by selecting for cells that are resistant to ferroptotic cell death. High cholesterol has been associated with increased risk of cancer but the underlying mechanism is not completely understood. Here, the authors show that a cholesterol metabolite induces metabolic reprogramming that generates ferroptosis-resistant cancer cells leading to increased tumour growth and metastasis.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
8.8
作者：
Feng, William W.;Wilkins, Owen;Kurokawa, Manabu
通讯作者：
Kurokawa, Manabu
影响因子：
19
作者：
Ackerman, Daniel;Simon, M. Celeste
通讯作者：
Simon, M. Celeste
DOI：
10.1126/science.aag1417
发表时间：
2017-03-24
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Castellano BM;Thelen AM;Moldavski O;Feltes M;van der Welle RE;Mydock-McGrane L;Jiang X;van Eijkeren RJ;Davis OB;Louie SM;Perera RM;Covey DF;Nomura DK;Ory DS;Zoncu R
通讯作者：
Zoncu R
影响因子：
45.3
作者：
Borgquist, Signe;Giobbie-Hurder, Anita;Thurlimann, Beat
通讯作者：
Thurlimann, Beat