Northern Blood Research Centre, Kolling Institution of Medical Research, The University of Sydney, St Leonards, Australia.
Children's Cancer Institute, Lowy Cancer Research, University of New South Wales, Randwick, Australia.
Leuk Lymphoma. 2020 Aug;61(8):1810-1822. doi: 10.1080/10428194.2020.1742899. Epub 2020 Apr 4.
Fatty acid synthesis is crucial in supporting the survival and proliferation of multiple forms of cancer. The high metabolic demands of fatty acid synthesis are regulated by the AMP-activated kinase and activity of the fatty acid synthase enzyme. In this study, the roles of these enzymes in diffuse large B-cell lymphoma (DLBCL) were investigated by genetic knock-down and pharmacological activation of AMP-activated kinase by metformin, and selective inhibition of fatty acid synthase using the novel drug Fasnall. We observed distinct heterogeneity and adaptive plasticity of lipid metabolism in a panel of DLBCL cell lines and demonstrate the therapeutic potential of inhibiting fatty acid synthesis in a subset of DLBCL cells. The translational relevance of these data is supported by the strong correlation between AMP-activated protein kinase expression in primary DLBCL samples and disease relapse. Inhibition of fatty acid synthase with Fasnall may represent a therapeutic option for DLBCL that preferentially subverts to fatty acid synthesis.
脂肪酸合成对于支持多种癌症的存活和增殖至关重要。脂肪酸合成的高代谢需求受 AMP 激活的蛋白激酶和脂肪酸合成酶的活性调节。在这项研究中，通过遗传敲除和二甲双胍对 AMP 激活的蛋白激酶的药理学激活，以及使用新型药物 Fasnall 选择性抑制脂肪酸合成，研究了这些酶在弥漫性大 B 细胞淋巴瘤 (DLBCL) 中的作用。我们观察到一系列 DLBCL 细胞系中脂质代谢的明显异质性和适应性可塑性，并证明了在亚组 DLBCL 细胞中抑制脂肪酸合成的治疗潜力。这些数据的转化相关性得到了主要 DLBCL 样本中 AMP 激活蛋白激酶表达与疾病复发之间的强相关性的支持。Fasnall 抑制脂肪酸合成可能代表了一种治疗 DLBCL 的选择，这种选择优先偏向脂肪酸合成。
