Biology subjects

Yee, E. U.

Publications and source records attributed to Yee, E. U..

3 recordsLinked to original sources

bioRxiv2025

Monensin and Its Analogs Exhibit Activity Against Breast Cancer Stem-Like Cells in an Organoid Model

Monensin (MON) is a polyether ionophore antibiotic of natural origin and is an FDA-approved drug for veterinary use. Recent studies have highlighted its potential anti-cancer activity in various in vitro and in vivo models. In this study, we evaluated the anti-breast cancer activity of MON and 37 synthetic analog compounds using cell monolayer and organoid models. Through a mini-ring cell viability assay, several compounds were identified that were more potent and selective against breast cancer cells compared to non-cancerous cells, surpassing the activity of parent MON. MON and these compounds induced significant DNA fragmentation, reduced cell migration, and downregulated SOX2 expression. Furthermore, MON and the most potent analog, compound 12, reduced the percentage of CD44+/CD24-/low stem-like cells and diminished cell self-renewal properties. Proteomics analyses revealed that several pathways, including extracellular matrix organization, were significantly dysregulated by MON and compound 12 in breast cancer cells. Among these, TIMP2, a protein associated with the suppression of tumor growth and metastasis, was identified as one of the most prominently upregulated proteins by MON and compound 12 in MDA-MB-231 cells. This finding was also validated in other breast cancer and melanoma cell lines. To simulate breast cancer metastasis to the brain, a human Hybrid Organoid System: Tumor in Brain Organoid (HOSTBO) model was developed. MON and compound 12 significantly reduced Ki-67 expression within the HOSTBOs, and compound 12 significantly downregulated SOX2 expression. Collectively, MON and compound 12 significantly reduced the proliferation of breast cancer stem-like cells in the organoid models, inhibited their migration, and dysregulated markers associated with stemness, demonstrating their potential as anti-metastatic agents and warranting further clinical development. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=137 SRC="FIGDIR/small/663311v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@388862org.highwire.dtl.DTLVardef@182072dorg.highwire.dtl.DTLVardef@1a55072org.highwire.dtl.DTLVardef@447150_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2022

Blocking mitochondrial alanine and pyruvate metabolism in hepatocytes worsens acetaminophen-induced liver injury in mice

Pyruvate is a critical intermediary metabolite in gluconeogenesis, lipogenesis, as well as NADH production. As a result, there is growing interest in targeting the mitochondrial pyruvate carrier (MPC) complex in liver and metabolic diseases. However, recent in vitro data indicate that MPC inhibition diverts glutamine/glutamate away from glutathione synthesis and toward glutaminolysis to compensate for loss of pyruvate oxidation, possibly sensitizing cells to oxidative insult. Here, we explored this using the clinically relevant acetaminophen (APAP) overdose model of acute liver injury, which is driven by oxidative stress. We report that MPC inhibition does indeed sensitize the liver to APAP-induced injury in vivo, but only with concomitant loss of alanine aminotransferase 2 (ALT2). Pharmacologic and genetic manipulation of neither MPC2 nor ALT2 alone affected APAP toxicity, but liver-specific double knockout (DKO) of these proteins significantly worsened the liver damage. Further investigation confirmed that DKO impaired glutathione synthesis and increased urea cycle flux, consistent with increased glutaminolysis. Furthermore, APAP toxicity was exacerbated by inhibition of both the MPC and ALT in vitro. Thus, increased glutaminolysis and susceptibility to oxidative stress requires loss of both the MPC and ALT2 in vivo and exacerbates them in vitro. Finally, induction of ALT2 reduced APAP-induced injury.

pharmacology and toxicology↗

bioRxiv2020

Exogenous phosphatidic acid reduces acetaminophen-induced liver injury in mice by activating the interleukin-6-Hsp70 axis through inter-organ crosstalk

We previously demonstrated that endogenous phosphatidic acid (PA) promotes liver regeneration after acetaminophen (APAP) hepatotoxicity in mice. Based on that, we hypothesized that exogenous PA is also beneficial. To test that, we treated mice with a toxic APAP dose at 0 h, followed by PA or vehicle at multiple timepoints. We then collected blood and liver at 6, 24, and 52 h. Post-treatment with PA protected against liver injury at 6 h, and the combination of PA and N-acetyl-cysteine (NAC) further reduced injury compared to NAC alone. Interestingly, PA had no effect on major early mechanisms of APAP toxicity, including APAP bioactivation, oxidative stress, JNK activation, and mitochondrial damage. However, transcriptomics revealed that PA activated interleukin-6 (IL-6) signaling in the liver, and IL-6 was increased in serum from PA-treated mice. Furthermore, PA did not protect against APAP in IL-6-deficient mice. In addition, IL-6 expression increased 18-fold in adipose tissue after PA, indicating that adipose tissue is a likely source of the increased IL-6 due to PA treatment. Surprisingly, however, exogenous PA did not alter regeneration, despite the widely accepted role of IL-6 in liver repair. These data reinforce the protective role of IL-6 in APAP hepatotoxicity, provide new insight into the role of IL-6 in liver regeneration, and indicate that exogenous PA or PA derivatives may one day be a useful adjunct treatment for APAP overdose with NAC.

pharmacology and toxicology↗