Targeting the fatty acid binding proteins disrupts multiple myeloma cell cycle progression and MYC signaling

Abstract

Multiple myeloma is an incurable plasma cell malignancy with only a 53% 5-year survival rate. There is a critical need to find new multiple myeloma vulnerabilities and therapeutic avenues. Herein, we identified and explored a novel multiple myeloma target: the fatty acid binding protein (FABP) family. In our work, myeloma cells were treated with FABP inhibitors (BMS3094013 and SBFI-26) and examined in vivo and in vitro for cell cycle state, proliferation, apoptosis, mitochondrial membrane potential, cellular metabolism (oxygen consumption rates and fatty acid oxidation), and DNA methylation properties. Myeloma cell responses to BMS309403, SBFI-26, or both, were also assessed with RNA sequencing (RNA-Seq) and proteomic analysis, and confirmed with western blotting and qRT-PCR. Myeloma cell dependency on FABPs was assessed using the Cancer Dependency Map (DepMap). Finally, MM patient datasets (CoMMpass and GEO) were mined for FABP expression correlations with clinical outcomes. We found that myeloma cells treated with FABPi or with FABP5 knockout (generated via CRISPR/Cas9 editing) exhibited diminished proliferation, increased apoptosis, and metabolic changes in vitro. FABPi had mixed results in vivo, in two pre-clinical MM mouse models, suggesting optimization of in vivo delivery, dosing, or type of FABP inhibitors will be needed before clinical applicability. FABPi negatively impacted mitochondrial respiration and reduced expression of MYC and other key signaling pathways in MM cells in vitro. Clinical data demonstrated worse overall and progression-free survival in patients with high FABP5 expression in tumor cells. Overall, this study establishes the FABP family as a potentially new target in multiple myeloma. In MM cells, FABPs have a multitude of actions and cellular roles that result in the support of myeloma progression. Further research into the FABP family in MM is warrented, especially into the effective translation of targeting these in vivo.

Inhibition of Acyl-CoA Synthetase Long Chain Isozymes Decreases Multiple Myeloma Cell Proliferation and Causes Mitochondrial Dysfunction

“…Cell Lines and Culture Conditions MM.1S (ATCC), RPMI-8226 (ATCC), and OPM-2 (DSMZ) cells, as well as luciferase-and gfpexpressing MM.1S (MM.1S gfp+/luc+ ) and MM.1R (MM.1R gfp+/luc ) cell lines were obtained and cultured as previously described (7) in RPMI-1640 basal media supplemented with 10% (15% for U266B1 cells) fetal bovine serum (FBS, VWR) with 1% antibiotic-antimycotic (ThermoFisher Scientific, Cat # 15240112) at a cell density of 4.166x10 5 cells/mL in tissue culture-treated T-75 flasks (VWR) (7). MM.1S gfp+/luc+ cells were used for experiments involving MM.1S cells unless otherwise stated.…”

“…XFe96 analyzer (Agilent Technologies), as previously described (7). Cells were also analyzed for total, mitochondrial, and glycolytic ATP production rates using a Seahorse XF ATP Production Rate Assay according to the manufacturer's instructions.…”

“…Indeed, alterations in MM cell glucose and glutamine metabolism have been shown to be tumor-supportive, and thus underscore targets in metabolic pathways as promising preclinical therapeutic targets (3). However, targeting myeloma cell fatty acid (FA) metabolism as a novel anti-myeloma avenue has only been suggested by a limited number of preclinical studies (4)(5)(6)(7)(8).…”

SBFI26 induces triple‐negative breast cancer cells ferroptosis via lipid peroxidation

“…Previous research has demonstrated that SBFI26 elicits intracellular apoptotic signals and induces apoptosis in PC3M cells by regulating the FABP5‐VEGF‐PPAR axis 10,23 . While previous studies have shown that SBFI26 can impede the proliferation of TNBC cells, its inhibitory effects on breast cancer have not yet been reported 47 …”

“…10,23 While previous studies have shown that SBFI26 can impede the proliferation of TNBC cells, its inhibitory effects on breast cancer have not yet been reported. 47 In this study, we investigated the impact of SBFI26 on breast cancer cell proliferation and analysed the transcriptome data following treatment with SBFI26 in TNBC cells. Through KEGG and GO analysis of transcriptomic data, it was observed that SBFI26 treatment up-regulated the expression of ferroptosis-related genes in TNBC cells compared to the control group.…”