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SBFI inhibitors reprogram transcriptomic landscape of prostate cancer leading to cell death [SBFI-1143]

ABSTRACT: Prostate cancer (PCa) remains the second leading cause of cancer-related deaths in the United States. Fatty acid-binding protein 5 (FABP5), a member of a class of intracellular lipid transporters, promotes PCa progression via enhanced lipid metabolism and trafficking of lipid ligands. Previous work from our group has shown that the small molecule FABP5 inhibitors based on the truxillic-acid monoester (TAMEs) scaffold reduce PCa growth. In the current study, we demonstrate that the third-generation FABP5 inhibitor SBFI-1143 significantly inhibited the viability and proliferation of PCa cells by arresting cells at the G0/G1 and G2/M phases of the cell cycle and inducing apoptosis and cell death compared to 1st and 2nd generation inhibitors. Stinkingly, SBFI-1143 efficiently inhibited the growth of PCa spheroids compared to its predecessor, SBFI-103. RNA sequencing and Gene Set Enrichment Analysis (GSEA) demonstrated that SBFI-1143 more effectively suppressed the activity of pathways involved in cell cycle progression, cell cycle division, and chromosome organization, while upregulated genes associated with the endoplasmic reticulum (ER) stress, responses to the topologically incorrect folded proteins, and regulating apoptosis compared to the SBFI-103. We further show that SBFI-1143 inhibits oxidative phosphorylation, a process on which PCa depends during cancer initiation and progression. Notably, SBFI-1143 treatment downregulated genes attributed to the subpopulation of PCa cells characterized by the lineage plasticity-related signature leading to trans-differentiation, recurrence, and poor cancer prognosis. Our findings demonstrate that SBFI-1143 significantly modifies the transcriptomic landscape of PCa and may serve as a potentially effective therapeutic option for PCa.

ORGANISM(S): Homo sapiens

PROVIDER: GSE297941 | GEO | 2025/12/17

REPOSITORIES: GEO

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Project description:Abstract Objective: Osteoarthritis (OA) is accompanied by severe and debilitating pain that current analgesics are unable to fully alleviate. A multitude of signaling molecules, pathways, and cells have been identified as regulators of OA pain. Fatty acid binding protein 5 (FABP5) regulates pain in other disease states and we hypothesized that it is involved in the regulation of OA pain. Design: This was a combined clinical and pre-clinical study. Human synovial and osteochondral tissues collected during total knee arthroplasty were subjected to immunohistochemical analyses to identify the spatial expression patterns of FAB5, COX1, COX2, and macrophages. In addition, synovial specimens were cultured the presence and absence of SBFI-103, a selective FABP5 inhibitor, and cytokines and chemokines levels were measured. The rat monoiodoacetate (MIA) model of OA was then enlisted to evaluate the efficacy of SBFI-103 in alleviating OA pain. Finally, RNAseq was performed to identify alterations in synovial gene expression in vehicle and SBFI-103 treated MIA rats. Results: FABP5 expression was present in clinical OA tissues, with higher expression seen higher grade OA and no apparent differences between genders. Furthermore, FABP5 staining colocalized with CD14+ cells, indicating a macrophage origin of FABP5. Synovial specimens secreted CCL2, IL6, IL8, CXCL1, MIF, and Serpin E1 in vitro and treatment with SBFI-103 attenuated CCL2, IL6, IL8, and CXCL1, but not MIF and Serpin E1. Twenty-eight days after MIA injection, rats exhibited histological joint degradation and significant incapacitance. Ketoprofen treatment partially reduced incapacitance and naproxen had no effect; however, SBFI-103 showed a dose dependent alleviation of incapacitance that was independent of cannabinoid or PPARα receptor activity. RNAseq analyses identified differential expression of >6,000 transcripts compared to contralateral controls in vehicle treated rats and only 513 after SBFI-103 treatment. Notably, CCL2, CCL7, CCL9, and CXCL1were upregulated in vehicle treated rats, but not those treated with SBFI-103, and this was confirmed with qPCR. Conclusions: Our results show that FABP5 is upregulated in clinical and preclinical OA tissues and that its inhibition lowers pronociceptive signaling and reduces OA pain, indicating that FABP5 inhibitors may constitute a novel class of analgesics to treat OA.

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SBFI inhibitors reprogram transcriptomic landscape of prostate cancer leading to cell death [SBFI-1143]

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