Biology subjects

Bowser, J. L.

Publications and source records attributed to Bowser, J. L..

3 recordsLinked to original sources

bioRxiv2025

Nicotinamide opposes ET-1's adverse effect on uterine decidualization via EDNRB

Endothelin-1 is involved in pathogenesis of preeclampsia. Mice (Edn1H/+) having excess endothelin-1 developed preeclampsia-like phenotypes during pregnancy in a maternal genotype-dependent manner. Here, we investigate whether decidualization is impaired in Edn1H/+ dams, and whether nicotinamide (a potent inhibitor of endothelin-1) exerts beneficial effect. We compared implantation sites between wild type (WT) and Edn1H/+ dams with or without nicotinamide treatment. Implantation sites of Edn1H/+ dams exhibited abnormal ectoplacental cone and sinusoids with reduced vascular density in mesometrial regions of deciduae. There was more VEGF in decidua of Edn1H/+ dams than WT dams. Markers of decidualization were decreased in Edn1H/+ dams. Nicotinamide supplementation corrected this abnormality. During differentiation (decidualization) of cultured human endometrial stomal cells, endothelin-1 impaired the upregulated expression of decidualization markers. The endothelin-1s effect was reversed by nicotinamide. These results show nicotinamide counteracts ET-1s detrimental effects on endometrial decidualization and has potential to improve embryo implantation and subsequent pregnancy outcomes.

developmental biology↗

bioRxiv2024

CD73 restrains mutant β-catenin oncogenic activity in endometrial carcinomas

Missense mutations in exon 3 of CTNNB1, the gene encoding {beta}-catenin, are associated with poor outcomes in endometrial carcinomas (EC). Clinically, CTNNB1 mutation status has been difficult to use as a predictive biomarker as {beta}-catenin oncogenic activity is modified by other factors, and these determinants are unknown. Here we reveal that CD73 restrains the oncogenic activity of exon 3 {beta}-catenin mutants, and its loss associates with recurrence. Using 7 patient-specific mutants, with genetic deletion or ectopic expression of CD73, we show that CD73 loss increases {beta}-catenin-TCF/LEF transcriptional activity. In cells lacking CD73, membrane levels of mutant {beta}-catenin decreased which corresponded with increased levels of nuclear and chromatin-bound mutant {beta}-catenin. These results suggest CD73 sequesters mutant {beta}-catenin to the membrane to limit its oncogenic activity. Adenosine A1 receptor deletion phenocopied increased {beta}-catenin-TCF/LEF activity seen with NT5E deletion, suggesting that the effect of CD73 loss on mutant {beta}-catenin is mediated via attenuation of adenosine receptor signaling. RNA-seq analyses revealed that NT5E deletion alone drives pro-tumor Wnt/{beta}-catenin gene expression and, with CD73 loss, {beta}-catenin mutants dysregulate zinc-finger and non-coding RNA gene expression. We identify CD73 as a novel regulator of oncogenic {beta}-catenin and help explain variability in patient outcomes in CTNNB1 mutant EC. O_FIG O_LINKSMALLFIG WIDTH=178 HEIGHT=200 SRC="FIGDIR/small/624183v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@f8e8f0org.highwire.dtl.DTLVardef@184e92aorg.highwire.dtl.DTLVardef@e7cb55org.highwire.dtl.DTLVardef@1d6421e_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG

cancer biology↗

bioRxiv2024

Inhibition of Androgen Receptor Exposes Replication Stress Vulnerability in Prostate Cancer

Standard initial systemic treatment for patients with metastatic prostate cancer includes agents that target androgen receptor (AR) signaling. Despite an initial positive response to these AR pathway inhibitors (ARPIs), acquired resistance remains a significant challenge. We show that treatment of AR-positive prostate cancer cells with the frontline ARPI enzalutamide induces DNA replication stress. Such stress is exacerbated by suppression of translesion DNA synthesis (TLS), leading to aberrant accumulation of single-stranded DNA (ssDNA) gaps and persistent DNA damage biomarkers. We further demonstrate that the TLS inhibitor, JH-RE-06, markedly sensitizes AR-positive prostate cancer cells, but not AR-negative benign cells, to enzalutamide in vitro. Combination therapy with enzalutamide and JH-RE-06 significantly suppresses cancer growth in a syngeneic murine tumor model over vehicle control or individual treatment groups. These findings suggest that AR inhibition broadly triggers DNA replication stress in hormone-sensitive prostate cancer, thereby exposing a unique vulnerability that can be exploited by a TLS-disrupting adjuvant for targeted therapy.

cancer biology↗