FABP5 REGULATES LIPOGENESIS AND TUMOR GROWTH IN LUNG ADENOCARCINOMA

K.A. GARCÍA; M.L. COSTA; M.E. MARTÍNEZ; G. ZADRA; D.M. MINSKY; E. LACUNZA; B. CÓRSICO; N. SCAGLIA

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Simposio; Tumor Metabolism and the Microenvironment; 2021

Worldwide, lung cancer has been the leading cause of cancer-relateddeath for decades. Unfortunately, targeted therapies have beenunsuccessful for most patients with lung adenocarcinoma (LUAD). Thus,new early markers and treatment options are required to increase theoverall survival and the number of patients who can benefit fromnovel therapies.Metabolism has emerged as a promising novel area for cancer therapy.Cancer cells undergo a metabolic reprogramming that copes with theincreased demand for macromolecule synthesis. Fatty acid (FA)synthesis is stimulated in various cancers and LUAD cells depend onthis pathway for cellular proliferation and tumorigenesis. Fatty acid-binding proteins (FABPs) are small intracellular proteinsthat bind FA and other hydrophobic ligands with high affinity. It hasbeen proposed that FABPs transport FA to different cellularcompartments, thus, to diverse metabolic fates. FABP5 has beenassociated with cancer onset and progression (especially in breastand prostate) mainly by regulating peroxisome proliferator activatedreceptors. However, its functions in lipid metabolism are not fullyunderstood. Using chemical inhibition, overexpression and knockdown models,we studied the role of FABP5 in channeling FA towards oxidation,lipid synthesis and regulation of nuclear factors in LUAD cell lines.Our results suggest that FABP5 is a master regulator of lipidmetabolism, diverting FA towards complex lipids synthesis. Moreover,FABP5 regulates de novo FA synthesis and the level of enzymesinvolved in this pathway (including fatty acid synthase andstearoyl-CoA desaturase 1). Unexpectedly, reporter assays suggestedthat FABP5 regulates gene expression in a PPAR-independent manner. RNA-Seq analysis showed that FABP5 inhibition triggers profoundchanges in A549 cells transcriptome not previously associated withthis protein. Consistently with the changes in lipid metabolism,FABP5 was required for cell cycle progression, in vitro migrationand in vivo tumor growth. Moreover, high expression of FABP5was associated with poor prognosis in patients with LUAD. Our results suggest that FABP5 regulates lipid metabolism, geneexpression and tumor progression in LUAD, placing it as a newputative marker/therapeutic target for this disease. p { margin-bottom: 0.1in; direction: ltr; line-height: 115%; text-align: justify; orphans: 2; widows: 2; background: transparent }a:link { color: #000080; so-language: zxx; text-decoration: underline }