Biology subjects

Reagan, M. R.

Publications and source records attributed to Reagan, M. R..

3 recordsLinked to original sources

bioRxiv2024

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

Multiple myeloma (MM) is an incurable cancer of plasma cells with a 5-year survival rate of 59%. Dysregulation of fatty acid (FA) metabolism is associated with MM development and progression; however, the underlying mechanisms remain unclear. Acyl-CoA synthetase long-chain family members (ACSLs) convert free long-chain fatty acids into fatty acyl-CoA esters and play key roles in catabolic and anabolic fatty acid metabolism. The Cancer Dependency Map data suggested that ACSL3 and ACSL4 were among the top 25% Hallmark Fatty Acid Metabolism genes that support MM fitness. Here, we show that inhibition of ACSLs in human myeloma cell lines using the pharmacological inhibitor Triascin C (TriC) causes apoptosis and decreases proliferation in a dose- and time-dependent manner. RNA-seq of MM.1S cells treated with TriC for 24 h showed a significant enrichment in apoptosis, ferroptosis, and ER stress. Proteomics of MM.1S cells treated with TriC for 48 h revealed that mitochondrial dysfunction and oxidative phosphorylation were significantly enriched pathways of interest, consistent with our observations of decreased mitochondrial membrane potential and increased mitochondrial superoxide levels. Interestingly, MM.1S cells treated with TriC for 24 h also showed decreased mitochondrial ATP production rates and overall lower cellular respiration. ImplicationsOverall, our data support the hypothesis that suppression of ACSL in human MM cells inhibit their growth and viability, indicating that ACSL proteins may be promising therapeutic targets in treating myeloma progression.

cancer biology↗

bioRxiv2022

The Fatty Acid Binding Protein Family Represents a Novel Target in Multiple Myeloma

BackgroundMultiple myeloma is an incurable plasma cell malignancy with only a 53% 5-year survival rate, highlighting a critical need for new multiple myeloma vulnerabilities and therapeutic avenues. Herein, we explored a novel multiple myeloma target: the fatty acid binding protein (FABP) family. MethodsMyeloma cells treated with FABP inhibitors (BMS3094013 and SBFI-26) were examined in vivo and in vitro for cell cycle, proliferation, apoptosis, mitochondrial membrane potential, cellular metabolism (oxygen consumption rates and fatty acid oxidation), and DNA methylation. Myeloma cell responses to BMS309403 and/or SBFI-26 were assessed with RNA-sequencing and proteomic analysis, and confirmed with western blotting and qRT-PCR. Myeloma cell dependency on FABPs was assessed using DepMap. Finally, MM patient datasets (CoMMpass and GEO) were mined for FABP expression correlations with clinical outcomes. ResultsMyeloma cells treated with FABPi or with FABP5 knockout (generated via CRISPR/Cas9 editing) exhibited diminished proliferation in vitro. FABPi had potent anti- tumor effects both in vitro and in vivo in two pre-clinical MM mouse models where increased mouse survival was observed. FABPi negatively impacted mitochondrial respiration and reduced expression of MYC and other key signaling pathways in MM cells. Clinical data demonstrated worse overall and progression-free survival in patients with high FABP5. ConclusionsThis study establishes the FABP family as a therapeutically actionable dependency in multiple myeloma with a multitude of actions and cellular roles that result in the support of myeloma progression. Statement of translational relevanceMultiple myeloma (MM) is an incurable disease of the plasma cell and MM patients require better treatments as soon as possible. The fatty acid binding protein (FABP) family plays a number of roles in cells, including supporting fatty acid oxidation, lipid shuttling and signal transduction. Here, we demonstrate with CoMMpass and other clinical data that FABPs represent a biomarker for aggressive disease in MM, and are a novel, targetable protein family expressed by myeloma cells. Pharmacologically inhibiting FABPs kills tumor cells and induces cell cycle arrest in vitro and in pre-clinical models. Mechanisms of action are multitudinous, as we discovered with RNA-sequencing, proteomic analysis, and phenotyping assays. Cell metabolism, cell signaling, cell stress, and epigenetic signatures were altered in MM cells when FABPs were inhibited. In summary, targeting FABP5 holds great therapeutic potential for killing diseased cells, with few negative off-target effects on healthy cells.

cancer biology↗

bioRxiv2020

Trpm8 modulates thermogenesis in a sex-dependent manner without influencing cold-induced bone loss

Trpm8 (transient receptor potential cation channel, subfamily M, member 8) is expressed by sensory neurons, and it is involved in the detection of cold temperatures. Increased TRPM8 activity triggers an increase in uncoupling protein 1 (Ucp1)-dependent brown adipose tissue (BAT) thermogenesis. Bone density and marrow adipose tissue are regulated by rodent housing temperature and brown adipose tissue, suggesting one mediator of this effect may be TRPM8. In order to test whether TRPM8 was involved in the co-regulation of thermogenesis and bone homeostasis, we examined the bone phenotypes of one-year-old Trpm8 knockout mice (Trpm8-KO) and then exposed them to a 4-week cold temperature challenge. Male Trpm8-KO mice had lower bone mineral density than WT, with smaller bone size (femur length and cross-sectional area) being the most striking finding, and exhibited a delayed cold acclimation with increased BAT expression of Ucp1, Dio2 and Cidea at the end of the study. In contrast to males, female Trpm8-KO mice had low vertebral bone microarchitectural parameters, but no genotype-specific alterations in body temperature. Interestingly, Trpm8 was not required for cold-induced trabecular bone loss in either sex, but may be required for cold-induced changes in marrow adiposity in males. Furthermore, bone marrow adipose tissue accumulation in females was significantly blunted by Trpm8 deletion. In summary, we identified sex differences in the role of TRPM8 in maintaining body temperature, bone density and marrow adipose tissue. Identifying mechanisms through which cold temperature and brown adipose tissue influence bone could help to ameliorate potential bone side effects of obesity treatments designed to stimulate thermogenesis.

physiology↗