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Biology subjects

Uray, I. P.

Publications and source records attributed to Uray, I. P..

2 recordsLinked to original sources
bioRxiv2025

G protein subtype preference dictates paroxetine-enhanced serotonin receptor response in normal breast epithelial cells

In the healthy mammary gland serotonin (5-HT) has a key role in shaping tissue morphology and regulating lactation and involution. Serotonin re-uptake inhibitors (SSRIs) alter the distribution of 5-HT across the cell membrane, but how increased extracellular 5-HT may impact breast cell homeostasis is unclear. We demonstrate that paroxetine reduces 5-HT levels in immortalized primary breast epithelial (HME-hTert) cells, mitigates free oxygen radical formation and decreases cell migration and proliferation. Accordingly, pathways related to cell cycle and DNA damage repair were underrepresented in the transciptomic profile of paroxetine-treated cells. On the other hand, enriched transcipts overrepresented genes affecting neural transmission and GPCR signaling, suggesting an increase in 5-HT receptor (5HTR) activation. As 5-HT induced the levels of both cAMP and inositol triphosphate (IP3), the contribution of individual 5HTRs were decyphered using receptor-selective agonists and antagonists. 5HTRs coupled to each G protein subtype were expressed and functional in HME-hTert cells. The activation of GS-coupled receptor 5HTR7 and antagonists of Gi- and Gq-coupled receptors 5HTR1D and 5HTR2B generally suppressed proliferation. The induction of cAMP levels by 5-HT was reduced by the 5HTR7 antagonist and IP3 induction was blocked by an 5HTR2B inhibitor, while the 5HTR1D antagonist further increased cAMP levels induced by 5-HT. Paroxetine-dependent growth suppression was reversed by inhibitors of GS-coupled 5HTR7, protein kinase A or adenylyl cyclase, and agonists of Gi or Gq-coupled receptors. These results suggest that the anti-proliferative responses to 5-HT in non-malignant breast cells align with the G protein preference of the receptors, and reveal potential benefits of repurposing receptor subtype-selective agents and SSRIs for cancer risk reduction. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=151 SRC="FIGDIR/small/658790v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1a4e2a4org.highwire.dtl.DTLVardef@1b9ea7org.highwire.dtl.DTLVardef@14cfe9dorg.highwire.dtl.DTLVardef@1e02960_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗
bioRxiv2022

Transglutaminase 2 associated with PI3K and PTEN in a putative membrane-bound signalosome platform blunts cell death

Atypically expressed transglutaminase 2 (TG2) has been identified as a poor prognostic factor in a variety of cancers. In this study, we evaluated the contribution of TG2 to the prolonged cell survival of differentiated acute promyelocytic leukaemia (APL) cells in response to the standard treatment with combined retinoic acid (ATRA) and arsenic trioxide (ATO). We report that one advantage of ATRA + ATO treatment compared to ATRA alone diminishes the amount of activated and non-activated CD11b/CD18 and CD11c/CD18 cell surface integrin receptors. These changes suppress ATRA-induced TG2 docking on the cytosolic part of CD18 {beta}2-integrin subunits and reduce cell survival. In addition, TG2 overexpresses and hyperactivates the phosphatidylinositol-3-kinase (PI3K), phospho-AKT S473, and phospho-mTOR S2481 signalling axis. mTORC2 acts as a functional switch between cell survival and death by promoting the full activation of AKT. We show that TG2 presumably triggers the formation of a signalosome platform, hyperactivates downstream mTORC2-AKT signalling, which in turn phosphorylates and inhibits the activity of FOXO3, a key pro-apoptotic transcription factor. In contrast, the absence of TG2 restores basic phospho-mTOR S2481, phospho-AKT S473, PI3K, and PTEN expression and activity, thereby sensitising APL cells to ATO-induced cell death. We conclude, that atypically expressed TG2 may serve as a hub, facilitating signal transduction via signalosome formation by the CD18 subunit with both PI3K hyperactivation and PTEN inactivation through the PI3K PTEN cycle in ATRA-treated APL cells.

cancer biology↗