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Fatty acid binding proteins contribute to multiple myeloma cell maintenance through regulation of Myc, the unfolded protein response, and metabolism

ABSTRACT: Multiple myeloma (MM) is an incurable plasma cell malignancy that causes anemia, osteolysis, hypercalcemia, and organ failure, with only a 53% 5-years survival rate. Herein, we present data demonstrating a novel target in MM: the fatty acid binding protein (FABP) family. In clinical data, FABP5 represented a novel biomarker for more aggressive cancer. FABP inhibitors decreased tumor burden in vitro and in vivo and increased survival in immunocompetent and immunocompromised mouse models. FABP5 was the most highly expressed FABP member in myeloma cells, and the most essential for their survival. CRISPR-Cas9 generated FABP5-KO MM.1S cells showed inhibited growth potential. RNA-sequencing and metabolic analysis identified new pathways of action for the FABPs, including MYC, the unfolded protein response (UPR), and metabolic changes. Collectively, our results demonstrate that FABPs comprise a novel, targetable, and safe, therapeutic avenue for MM and other cancers, and suggest inhibiting FABPs may be worthy of further study.

ORGANISM(S): Homo sapiens

PROVIDER: GSE190699 | GEO | 2022/12/11

REPOSITORIES: GEO

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Mitochondrial integrity regulated by FABP5 is a cell-intrinsic checkpoint for Treg suppressive function

Project description:Regulatory T cells (Tregs) negatively regulate immune-mediated inflammation that is essential for preventing autoimmunity, but which can be detrimental in cancer. Central to Treg activation are changes in lipid metabolism to support their survival and function. Fatty acid binding proteins (FABPs) are a family of lipid chaperones required to facilitate the uptake and trafficking of intracellular lipids. One family member, FABP5, is expressed in certain T cell subsets, but its function remains elusive. We show here that in Tregs, FABP5 inhibition causes mitochondrial defects, underscored by decreased OXPHOS, lipid elongation and desaturation, and loss of cristae structure, which augment their suppressive function. Mitochondrial dysfunction after FABP5 inhibition results in mtDNA release and consequent cGAS/STING-dependent type I IFN signaling, which induces increased production of the regulatory cytokine IL-10, promoting Treg cell suppressive activity. Together these data reveal that FABP5 acts as a gatekeeper of mitochondrial health to control Treg cell function.

2019-12-26 | GSE126245 | GEO

Fatty Acid Binding Protein 5 is a Novel Target in Multiple Myeloma

Project description:To identify protein changes in human myeloma cancer cells resulting from FABP inhibition, we treated GFP+/Luc+MM.1S cells with the single inhibitors (50 µM BMS309405 or 50 µM SBFI-26) or the combination (50 µM of each) for 48 hour, isolated total cell proteins, and performed a mass spectrometry-based proteomic analysis.

2023-01-12 | PXD032829 | Pride

Gastric cancer cells exploit FABP5 via the PD-L1/TNF/IL-17 signaling axis

Project description:Background: Gastric cancer (GC) is the second most lethal cancer globally and is associated with poor prognosis. Fatty acid-binding proteins (FABPs) can regulate the biological properties of carcinoma cells. FABP5 is overexpressed in many types of cancers; however, the role and mechanism of FABP5 in GC are still unclear. Aim: In this study, we aimed to evaluate the clinical and biological function of FABP5 in GC. Methods: We assessed FABP5 expression using immunohistochemical analysis of 79 GC patients and evaluated its biological functions following in vitro and in vivo ectopic expression. FABP5 targets relevant to GC progression were determined using RNA sequencing (RNA-seq) analyses. Results: Elevated FABP5 expression was closely related to poor outcomes, and ectopic expression of FABP5 promoted GC cell proliferation, invasion, migration, and carcinogenicity, suggesting its potential tumor-promoting role in GC. Additionally, RNA-seq analysis indicated that FABP5 activates immune-related pathways, including cytokine–cytokine receptor-interaction pathways, interleukin-17 signaling, and tumor necrosis factor signaling, suggesting an important rationale for the possible development of therapies combining FABP5-targeted drugs with immunotherapeutics. Conclusion: These findings highlight the biological mechanisms and clinical implications of FABP5 in GC and suggest its potential as an adverse prognostic factor and/or therapeutic target.

2023-12-31 | GSE218422 | GEO

Functional role and therapeutic targeting of p21-associated kinase 4 (PAK4) in Multiple Myeloma

Project description:Dysregulated oncogenic serine/threonine kinases play a pathological role in diverse forms of malignancies, including multiple myeloma (MM), and thus represent potential therapeutic targets. Here, we evaluated the biological and functional role of p21-activated kinase 4 (PAK4), and its potential as a new target in MM for clinical applications. PAK4 promoted MM cell growth and survival via activation of MM survival signaling pathways, including the MEK-ERK pathway. Furthermore, treatment with orally bioavailable PAK4 allosteric modulator (KPT-9274) significantly impacted MM cell growth and survival in a large panel of MM cell lines and primary MM cells alone and in the presence of bone marrow microenvironment. Intriguingly, we have identified FGFR3 as a novel binding partner of PAK4 and observed significant activity of KPT-9274 against t(4;14)-positive MM cells. These data support PAK4 as an oncogene in myeloma, and provide the rationale for the clinical evaluation of PAK4 modulator in myeloma.

2017-01-19 | GSE93745 | GEO

Acupuncture Synergized With Bortezomib Improves Survival of Multiple Myeloma Mice via Decreasing Metabolic Ornithine

Project description:Multiple myeloma (MM) is a hematological malignancy worldwide in urgent need for novel therapeutic strategies. Since Velcade (bortezomib) was approved for the treatment of relapsed/refractory MM in 2003, we have seen considerable improvement in extending MM patient survival. However, most patients are fraught with high recurrence rate and incurability. Acupuncture is known for alleviating patient symptoms and improving the quality of life, but it is not well investigated in MM, especially in combination with bortezomib. In this study, we employed LC-MS and UHPLC-MS together with bioinformatics methods to test blood samples from 5TMM3VT MM murine model mice with four different treatments (control (C) group, bortezomib (V) treatment group, acupuncture (A) group and combined (VA) group). MM mice in group VA had longer survival time than mice in group A or group V. Joint pathway analysis indicated the underlying arginine and proline metabolism pathway among the 32 significantly decreased metabolites in group VA. CCK-8 assay and in vivo experiments validated that ornithine, the metabolite of arginine, promoted MM cell proliferation. In addition, gene expression omnibus (GEO) database analysis suggested that MM patients with higher ornithine decarboxylase 1 (ODC1) expression were evidently associated with poor overall survival. In summary, this study demonstrates the synergistic effects of acupuncture and bortezomib on extending the survival of MM model mice and provides potential therapeutic targets in the treatment of MM.

2022-02-21 | MTBLS3487 | MetaboLights

Chidamide used in MM primary cells [RNA-seq]

Project description:Most patients with multiple myeloma (MM) will eventually relapse and current treatments have limited effect. Herein, we demonstrate that succinate dehydrogenase subunitA (SDHA) was low expressed in MM patients, and patients with SDHA relatively high expression had long overall survival and progression-free survival. Furthermore, SDHA high expression inhibited proliferation and invasion in multiple myeloma (MM) cell lines and enhanced the anti-tumor and synergistic effect of chemotherapeutics. We conducted transcriptome comparison of BMMCs of three MM patients treated with DMSO or chidamide.

2020-09-09 | GSE156501 | GEO

CRIP1 involves the pathogenesis of multiple myeloma via dual-regulation of proteasome and autophagy

Project description:Multiple myeloma (MM) is an incurable hematological malignancy of plasma cells. The maintenance of protein homeostasis is critical for the survival of MM cells. The excess paraprotein in MM cells undergoes clearance through proteasomes or lysosomes, two inter-connected yet independent pathways. While proteasome inhibitors (PIs) serve as fundamental agents significantly improving patient outcomes, heightened autophagy activity diminishes sensitivity to PI treatment.Elevated CRIP1 levels serve as a biomarker for relapsed/refractory MM and correlate with shorter overall patient survival. To further comprehend the role of CRIP1 in multiple myeloma pathogenesis, we conducted transcriptome sequencing.

2023-11-27 | GSE248339 | GEO

RUNX proteins desensitize multiple myeloma to lenalidomide via protecting IKZFs from degradation

Project description:Ikaros family zinc finger protein 1 and 3 (IKZF1 and IKZF3) are transcription factors that promote multiple myeloma (MM) proliferation. The immunomodulatory imide drug (IMiD) lenalidomide promotes myeloma cell death via Cereblon (CRBN)-dependent ubiquitylation and proteasome-dependent degradation of IKZF1 and IKZF3. Although IMiDs have been used as first-line drugs for MM, the overall survival of refractory MM patients remains poor and demands the identification of novel agents to potentiate the therapeutic effect of IMiDs. Using an unbiased screen based on mass spectrometry, we identified the Runt-related transcription factor 1 and 3 (RUNX1 and RUNX3) as interactors of IKZF1 and IKZF3. Interaction with RUNX1 and RUNX3 inhibits CRBN-dependent binding, ubiquitylation and degradation of IKZF1 and IKZF3 upon lenalidomide treatment. Inhibition of RUNXs, via genetic ablation or a small molecule (AI-10-104), results in sensitization of myeloma cell lines and primary tumors to lenalidomide. Thus, RUNX inhibition represents a valuable therapeutic opportunity to potentiate IMiDs therapy for the treatment of multiple myeloma.

2020-04-13 | GSE123660 | GEO

Systems medicine dissection of chromosome 1q amplification reveals a novel PBX1-FOXM1 axis for targeted therapy in multiple myeloma

Project description:Here we report the use of high-throughput sequencing technologies (RNA-seq, ChIP-seq) to identify the molecular programme of PBX1 and FOXM1 in multiple myeloma cells (MM1S, U266 cell lines). We performed Chromatin Immunoprecipitation followed by sequencing (ChIP-seq) against PBX1 in MM1S and U266 cells (n=2). In addition, we identifed the transcriptome of PBX1-depleted and FOXM1-depleted myeloma cells 3 days after transduction with shRNA-expressing lentiviral vectors. Molecular characterization revealed PBX1 as a novel epigenetic regulator of myeloma cell survival and proliferation. PBX1 directly and unilaterally controls the FOXM1 transcriptional programme and, together,they regulate the high-risk transcriptional signature of chr1q-amplified cells. Pharmacological inhibition of the unified PBX1-FOXM1 axis with thiostrepton showed selectivity against chr1q-amplified MM. Altogether, these data reveal PBX1-FOXM1 axis as a novel therapeutic avenue against chr1q-amplified MM.

2022-01-16 | GSE165060 | GEO

Fatty acid binding proteins shape the cellular response to activation of the glucocorticoid receptor

Project description:Glucocorticoids are steroid hormones that are essential for life in mammals. Therapeutically, they are some of the most cost-effective drugs for the treatment of inflammatory diseases ranging from skin rashes to COVID-19, but their use is limited by adverse effects. Glucocorticoids exert their effects via the glucocorticoid receptor, a type I nuclear hormone receptor which modulates gene expression. The transcriptional activity of some related, but nuclear restricted, type II nuclear hormone receptors can be enhanced by a family of intracellular transport proteins, the fatty acid binding proteins (FABPs). We find that the transcriptional activity of the GR can be altered by a sub-set of FABP family members dependent on the GR-ligand. The ability of some FABPs to selectively promote or limit the transcriptional activity of the GR in a ligand-dependent manner could facilitate the discovery of drugs that narrow GR activity to only the desired subset of therapeutically relevant genes.

2021-07-22 | GSE180341 | GEO

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