ELOVL5 是前列腺癌中一种关键且可靶向的脂肪酸延长酶,Cancer Research

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ELOVL5 是前列腺癌中一种关键且可靶向的脂肪酸延长酶
Cancer Research ( IF 12.5 ) Pub Date : 2021-04-01 , DOI: 10.1158/0008-5472.can-20-2511
Margaret M Centenera _{1,

2,

3} , Julia S Scott _{1,

2,

3} , Jelle Machiels ₄ , Zeyad D Nassar _{1,

2,

3} , Deanna C Miller _{1,

2,

3} , Irene Zinonos _{1,

5} , Jonas Dehairs ₄ , Ingrid J G Burvenich _{6,

7} , Giorgia Zadra ₈ , Paolo M Chetta _{8,

9} , Clyde Bango ₈ , Emma Evergren ₁₀ , Natalie K Ryan _{1,

3} , Joanna L Gillis _{1,

3} , Chui Yan Mah _{1,

2,

3} , Terence Tieu _{11,

12} , Adrienne R Hanson ₁ , Ryan Carelli ₁₃ , Katarzyna Bloch ₄ , Vasilios Panagopoulos _{1,

3} , Etienne Waelkens ₁₄ , Rita Derua ₁₄ , Elizabeth D Williams ₁₅ , Andreas Evdokiou _{1,

5} , Anna Cifuentes-Rius ₁₁ , Nicolas H Voelcker _{11,

12,

16} , Ian G Mills _{10,

17} , Wayne D Tilley _{1,

2} , Andrew M Scott _{6,

7,

18,

19} , Massimo Loda ₁₃ , Luke A Selth _{1,

2,

20} , Johannes V Swinnen ₄ , Lisa M Butler _{1,

2,

3}

Affiliation

University of Adelaide Medical School, Adelaide, SA, Australia.
Freemasons Foundation Centre for Men's Health, Adelaide, SA, Australia.
South Australian Health and Medical Research Institute, Adelaide, SA, Australia.
Department of Oncology, Laboratory of Lipid Metabolism and Cancer, KU Leuven, Leuven, Belgium.
Basil Hetzel Institute, Queen Elizabeth Hospital, SA, Australia.
Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, VIC, Australia.
School of Cancer Medicine, La Trobe University, Melbourne, VIC, Australia.
Dana-Farber Cancer Institute, Boston, Massachusetts.
University of Milan, Milan, Italy.
Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK.
Drug Delivery, Disposition and Dynamics, Monash University, Parkville, VIC, Australia.
Commonwealth Scientific and Industrial Research Organisation (CSIRO), Clayton, VIC, Australia.
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York-Presbyterian Hospital, New York, New York.
Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
Australian Prostate Cancer Research Centre - Queensland, Queensland University of Technology (QUT), Princess Alexandra Hospital, Translational Research Institute, Brisbane, QLD, Australia.
Melbourne Centre for Nanofabrication, Victorian Node of the Australian National Fabrication Facility, Clayton, VIC, Australia.
Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.
Department of Medicine, University of Melbourne, Melbourne, VIC, Australia.
Department of Molecular Imaging and Therapy, Austin Health, Melbourne, VIC, Australia.
Flinders Health and Medical Research Institute, Flinders University, Bedford Park, South Australia, Australia.

雄激素受体 (AR) 是前列腺癌的关键致癌驱动因素，尽管实施了新型 AR 靶向疗法，但转移性疾病的结果仍然令人沮丧。迫切需要更好地了解雄激素调节的细胞过程，以通过新的治疗漏洞更有效地靶向前列腺癌细胞的 AR 依赖性。转录组学研究一致将脂质代谢确定为前列腺癌中增强的 AR 信号传导的标志，但 AR 与脂质组之间的关系仍未确定。使用基于质谱的脂质组学，这项研究揭示了来自前列腺癌细胞和患者来源的外植体的磷脂中脂肪酰基链长度的增加，这是脂质代谢最显着的雄激素调节变化之一。在前列腺癌细胞、异种移植物和临床肿瘤中证明了有效和直接的 AR 介导的 ELOVL 脂肪酸延长酶 5 (ELOVL5) 是一种催化脂肪酸延长的酶。对大规模数据集中 mRNA 和蛋白质的评估显示，与非恶性前列腺相比，ELOVL5 是前列腺癌中表达和上调的主要 ELOVL。ELOVL5 耗竭显着改变了线粒体形态和功能，导致活性氧的过量生成，从而抑制前列腺癌细胞增殖、3D 生长以及体内肿瘤生长和转移。补充单不饱和脂肪酸 cis-vaccenic 酸（ELOVL5 延长的直接产物）逆转了 ELOVL5 敲低的氧化应激和相关的细胞增殖和迁移效应。总的来说，这些结果将脂质延长确定为前列腺癌中的促肿瘤代谢途径，该途径受雄激素调节，对转移至关重要，并可通过 ELOVL5 靶向。意义：本研究将磷脂延长确定为雄激素作用的新代谢靶点，对前列腺肿瘤转移至关重要。

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ELOVL5 Is a Critical and Targetable Fatty Acid Elongase in Prostate Cancer

The androgen receptor (AR) is the key oncogenic driver of prostate cancer, and despite implementation of novel AR targeting therapies, outcomes for metastatic disease remain dismal. There is an urgent need to better understand androgen-regulated cellular processes to more effectively target the AR dependence of prostate cancer cells through new therapeutic vulnerabilities. Transcriptomic studies have consistently identified lipid metabolism as a hallmark of enhanced AR signaling in prostate cancer, yet the relationship between AR and the lipidome remains undefined. Using mass spectrometry–based lipidomics, this study reveals increased fatty acyl chain length in phospholipids from prostate cancer cells and patient-derived explants as one of the most striking androgen-regulated changes to lipid metabolism. Potent and direct AR-mediated induction of ELOVL fatty acid elongase 5 (ELOVL5), an enzyme that catalyzes fatty acid elongation, was demonstrated in prostate cancer cells, xenografts, and clinical tumors. Assessment of mRNA and protein in large-scale data sets revealed ELOVL5 as the predominant ELOVL expressed and upregulated in prostate cancer compared with nonmalignant prostate. ELOVL5 depletion markedly altered mitochondrial morphology and function, leading to excess generation of reactive oxygen species and resulting in suppression of prostate cancer cell proliferation, 3D growth, and in vivo tumor growth and metastasis. Supplementation with the monounsaturated fatty acid cis-vaccenic acid, a direct product of ELOVL5 elongation, reversed the oxidative stress and associated cell proliferation and migration effects of ELOVL5 knockdown. Collectively, these results identify lipid elongation as a protumorigenic metabolic pathway in prostate cancer that is androgen-regulated, critical for metastasis, and targetable via ELOVL5. Significance: This study identifies phospholipid elongation as a new metabolic target of androgen action that is critical for prostate tumor metastasis.

更新日期：2021-04-01

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