Instituto de Investigaciones Bioquímicas de la Plata (INIBIOLP), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Médicas, Universidad Nacional de La Plata (UNLP), La Plata, Buenos Aires, Argentina.
Centro de Investigaciones Inmunológicas Básicas y Aplicadas (CINIBA), Comisión de Investigaciones Científicas de la Provincia de Buenos Aires (CICPBA), Facultad de Ciencias Médicas, Universidad Nacional de La Plata (UNLP), La Plata, Buenos Aires, Argentina.
Life Sci. 2022 Jul 15;301:120621. doi: 10.1016/j.lfs.2022.120621. Epub 2022 May 8.
Lung cancer is the leading cause of cancer-related death. Unfortunately, targeted-therapies have been unsuccessful for most patients with lung adenocarcinoma (LUAD). Thus, new early biomarkers and treatment options are a pressing need. Fatty acid binding protein 5 (FABP5) has been associated with various types of cancers. Its contribution to LUAD onset, progression and metabolic reprogramming is, however, not fully understood. In this study we assessed the importance of FABP5 in LUAD and its role in cancer lipid metabolism.
By radioactive labeling and metabolite quantification, we studied the function of FABP5 in fatty acid metabolism using genetic/pharmacologic inhibition and overexpression models in LUAD cell lines. Flow cytometry, heterologous transplantation and bioinformatic analysis were used, in combination with other methodologies, to assess the importance of FABP5 for cellular proliferation in vitro and in vivo and in patient survival.
We show that high expression of FABP5 is associated with poor prognosis in patients with LUAD. FABP5 regulates lipid metabolism, diverting fatty acids towards complex lipid synthesis, whereas it does not affect their catabolism in vitro. Moreover, FABP5 is required for de novo fatty acid synthesis and regulates the expression of enzymes involved in the pathway (including FASN and SCD1). Consistently with the changes in lipid metabolism, FABP5 is required for cell cycle progression, migration and in vivo tumor growth.
Our results suggest that FABP5 is a regulatory hub of lipid metabolism and tumor progression in LUAD, placing it as a new putative therapeutic target for this disease.
肺癌是癌症相关死亡的主要原因。不幸的是，大多数肺腺癌（LUAD）患者的靶向治疗都不成功。因此，新的早期生物标志物和治疗选择是迫切需要的。脂肪酸结合蛋白 5（FABP5）与多种类型的癌症有关。然而，其对 LUAD 发病、进展和代谢重编程的贡献尚不完全清楚。在这项研究中，我们评估了 FABP5 在 LUAD 中的重要性及其在癌症脂质代谢中的作用。
通过放射性标记和代谢物定量，我们使用 LUAD 细胞系中的遗传/药理学抑制和过表达模型研究了 FABP5 在脂肪酸代谢中的功能。流式细胞术、异基因移植和生物信息学分析与其他方法相结合，用于评估 FABP5 在体外和体内细胞增殖以及患者生存中的重要性。
我们表明，FABP5 的高表达与 LUAD 患者的预后不良相关。FABP5 调节脂质代谢，将脂肪酸转向复杂脂质合成，而在体外不影响其分解代谢。此外，FABP5 是从头脂肪酸合成所必需的，并调节该途径中涉及的酶的表达（包括 FASN 和 SCD1）。与脂质代谢的变化一致，FABP5 是细胞周期进程、迁移和体内肿瘤生长所必需的。
我们的结果表明，FABP5 是 LUAD 中脂质代谢和肿瘤进展的调节枢纽，将其作为该疾病的新潜在治疗靶点。
