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Ketogenic HMG-CoA lyase and its product β-hydroxybutyrate promote pancreatic cancer progression.
The EMBO Journal ( IF 11.4 ) Pub Date : 2022-03-21 , DOI: 10.15252/embj.2021110466
Victoire Gouirand 1, 2, 3, 4 , Tristan Gicquel 1, 2, 3, 4 , Evan C Lien 5 , Emilie Jaune-Pons 1, 2, 3, 4 , Quentin Da Costa 1, 2, 3, 4 , Pascal Finetti 1, 2, 3, 4 , Elodie Metay 1, 2, 3, 4 , Camille Duluc 1, 2, 3, 4 , Jared R Mayers 5 , Stephane Audebert 1, 2, 3, 4 , Luc Camoin 1, 2, 3, 4 , Laurence Borge 1, 2, 3, 4 , Marion Rubis 1, 2, 3, 4 , Julie Leca 1, 2, 3, 4 , Jeremy Nigri 1, 2, 3, 4 , François Bertucci 1, 2, 3, 4 , Nelson Dusetti 1, 2, 3, 4 , Juan L Iovanna 1, 2, 3, 4 , Richard Tomasini 1, 2, 3, 4 , Ghislain Bidaut 1, 2, 3, 4 , Fabienne Guillaumond 1, 2, 3, 4 , Matthew G Vander Heiden 5, 6 , Sophie Vasseur 1, 2, 3, 4
Affiliation  

Pancreatic ductal adenocarcinoma (PDA) tumor cells are deprived of oxygen and nutrients and therefore must adapt their metabolism to ensure proliferation. In some physiological states, cells rely on ketone bodies to satisfy their metabolic needs, especially during nutrient stress. Here, we show that PDA cells can activate ketone body metabolism and that β-hydroxybutyrate (βOHB) is an alternative cell-intrinsic or systemic fuel that can promote PDA growth and progression. PDA cells activate enzymes required for ketogenesis, utilizing various nutrients as carbon sources for ketone body formation. By assessing metabolic gene expression from spontaneously arising PDA tumors in mice, we find HMG-CoA lyase (HMGCL), involved in ketogenesis, to be among the most deregulated metabolic enzymes in PDA compared to normal pancreas. In vitro depletion of HMGCL impedes migration, tumor cell invasiveness, and anchorage-independent tumor sphere compaction. Moreover, disrupting HMGCL drastically decreases PDA tumor growth in vivo, while βOHB stimulates metastatic dissemination to the liver. These findings suggest that βOHB increases PDA aggressiveness and identify HMGCL and ketogenesis as metabolic targets for limiting PDA progression.

中文翻译:

生酮 HMG-CoA 裂解酶及其产物 β-羟基丁酸促进胰腺癌进展。

胰腺导管腺癌 (PDA) 肿瘤细胞缺乏氧气和营养,因此必须调整其代谢以确保增殖。在某些生理状态下,细胞依赖酮体来满足其代谢需求,尤其是在营养压力期间。在这里,我们表明 PDA 细胞可以激活酮体代谢,并且 β-羟基丁酸 (βOHB) 是一种替代的细胞内在或全身燃料,可以促进 PDA 的生长和进展。PDA细胞激活生酮所需的酶,利用各种营养物质作为酮体形成的碳源。通过评估小鼠自发产生的 PDA 肿瘤的代谢基因表达,我们发现与正常胰腺相比,参与生酮作用的 HMG-CoA 裂解酶 (HMGCL) 是 PDA 中最失调的代谢酶之一。HMGCL 的体外消耗会阻碍迁移、肿瘤细胞侵袭和不依赖贴壁的肿瘤球体压实。此外,破坏 HMGCL 会大大降低体内 PDA 肿瘤的生长,而 βOHB 会刺激向肝脏的转移扩散。这些发现表明,βOHB 增加了 PDA 的攻击性,并将 HMGCL 和生酮确定为限制 PDA 进展的代谢靶点。
更新日期:2022-03-21
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