Fatty Acid Uptake and Lipid Storage Induced by HIF-1α Contribute to Cell Growth and Survival after Hypoxia-Reoxygenation

被引：547

作者：

Bensaad, Karim ^{[1
]}

Favaro, Elena ^{[1
]}

Lewis, Caroline A. ^{[2
]}

Peck, Barrie ^{[2
]}

Lord, Simon ^{[1
]}

Collins, Jennifer M. ^{[3
]}

Pinnick, Katherine E. ^{[3
]}

Wigfield, Simon ^{[1
]}

Buffa, Francesca M. ^{[1
]}

Li, Ji-Liang ^{[1
]}

Zhang, Qifeng ^{[5
]}

Wakelam, Michael J. O. ^{[5
]}

Karpe, Fredrik ^{[3
,4
]}

Schulze, Almut ^{[2
,6
]}

Harris, Adrian L. ^{[1
]}

机构：

[1] Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, CRUK Hypoxia & Angiogenesis Grp, Oxford OX3 9DS, England

[2] Canc Res UK, London Res Inst, Gene Express Anal Lab, London WC2A 3LY, England

[3] Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX3 7LJ, England

[4] OUH Trust, Churchill Hosp, NIHR Oxford Biomed Res Ctr, Oxford OX3 7LF, England

[5] Babraham Inst, Cambridge CB22 3AT, England

[6] Theodor Boveri Inst, Bioctr, Dept Biochem & Mol Biol, D-97074 Wurzburg, Germany

来源：

CELL REPORTS | 2014年 / 9卷 / 01期

基金：

英国生物技术与生命科学研究理事会;

关键词：

CANCER-CELL; TRIGLYCERIDE ACCUMULATION; BINDING PROTEIN; BETA-OXIDATION; COMPLEX-III; LIPOGENESIS; METABOLISM; RESISTANCE; PROLIFERATION; ANGIOGENESIS;

D O I：

10.1016/j.celrep.2014.08.056

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

An in vivo model of antiangiogenic therapy allowed us to identify genes upregulated by bevacizumab treatment, including Fatty Acid Binding Protein 3 (FABP3) and FABP7, both of which are involved in fatty acid uptake. In vitro, both were induced by hypoxia in a hypoxia-inducible factor-1 alpha (HIF-1 alpha)-dependent manner. There was a significant lipid droplet (LD) accumulation in hypoxia that was time and O-2 concentration dependent. Knockdown of endogenous expression of FABP3, FABP7, or Adipophilin (an essential LD structural component) significantly impaired LD formation under hypoxia. We showed that LD accumulation is due to FABP3/7-dependent fatty acid uptake while de novo fatty acid synthesis is repressed in hypoxia. We also showed that ATP production occurs via beta-oxidation or glycogen degradation in a cell-type-dependent manner in hypoxia-reoxygenation. Finally, inhibition of lipid storage reduced protection against reactive oxygen species toxicity, decreased the survival of cells subjected to hypoxia-reoxygenation in vitro, and strongly impaired tumorigenesis in vivo.

引用

页码：349 / 365

页数：17

共 62 条

[1] The Lipogenesis Pathway as a Cancer Target [J].