Biology subjects

Farsinejad, S.

Publications and source records attributed to Farsinejad, S..

3 recordsLinked to original sources

bioRxiv2025

Suppression of Ovarian Cancer Cell Proliferation is Associated with Upregulation of Cell-Matrix Adhesion Programs and Integrin-β4-Induced Cell Protection from Cisplatin.

The role of extracellular matrix adhesion components in modulation of the treatment sensitivity of ovarian cancer (OC) cells is not well understood. Analysis of ovarian cancer TCGA gene expression data sets revealed an inverse correlation between genes involved in cell-cycle progression and extracellular matrix interactions including laminin-binding receptor integrin {beta}4, a major component of extracellular matrix adhesion. Gene ontology analysis also showed that in patient populations with low integrin {beta}4 expression, cell cycle-related programs were activated, while in populations with high expression of integrin {beta}4, the activation of these cell cycle programs was lower. Suppression of proliferation with CDK4/6 inhibitor Palbociclib stimulated integrin {beta}4 expression and induced protection against cisplatin in cells naturally expressing low levels of integrin {beta}4. Additionally, ovarian cancer patient-derived organoids showed reduced cisplatin sensitivity when pretreated with Palbociclib. Our data also showed that integrin {beta}4 overexpression decreased ovarian cancer cell proliferation and at the same time, attenuated cisplatin response. Our investigations reveal that expression of integrin {beta}4 inversely correlates with cell cycle progression programs, whether observed in expression data of OC patient samples or in various OC cell lines. Consistently with these results, the overexpression of ITGB4 gene in ovarian cancer cell lines correlated with reduced cell proliferation rates and diminished sensitivity to cisplatin, supporting the idea that integrin {beta}4 and likely its matrix ligands play critical roles in the regulation of cellular growth and chemoresistance of ovarian cancer cells.

cancer biology↗

bioRxiv2023

The Dietary Supplement Taurine Suppresses Ovarian Cancer Growth

Taurine, a non-proteogenic amino acid, and commonly used nutritional supplement can protect various tissues from degeneration associated with the action of the DNA-damaging chemotherapeutic agent cisplatin. Whether and how taurine protects human ovarian cancer (OC) cells from DNA damage caused by cisplatin is not well understood. We have found that OC ascites-derived cells contained significantly more intracellular taurine than cell cultures modeling OC. In culture, elevation of intracellular taurine concentration to OC ascites-cells-associated levels suppressed proliferation of various OC cell lines and patient-derived organoids, reduced glycolysis, and induced cell protection from cisplatin. Taurine cell protection was associated with decreased DNA damage in response to cisplatin. A combination of RNA sequencing, reverse phase protein arrays, live-cell microscopy, flow cytometry, and biochemical validation experiments provided evidence for taurine-mediated induction of mutant- or wild-type p53 binding to DNA, and activation of p53 effectors involved in negative regulation of the cell cycle (p21), and glycolysis (TIGAR). Paradoxically, taurines suppression of cell proliferation was associated with activation of pro-mitogenic signal transduction including ERK, mTOR, and increased mRNA expression of major DNA damage sensing molecules such as DNAPK, ATM and ATR. While inhibition of ERK or p53 did not interfere with taurines ability to protect cells from cisplatin, suppression of mTOR with Torin2, a clinically relevant inhibitor that also targets DNAPK and ATM/ATR, broke taurines cell protection. Our studies implicate that elevation of intracellular taurine could suppress cell growth, metabolism, and activate cell protective mechanisms involving mTOR and DNA damage sensing signal transduction.

cancer biology↗

bioRxiv2022

Extracellular Matrix Levels Modulate Outgrowths Dynamics in Ovarian Cancer.

Ovarian carcinoma (OC) forms outgrowths that extend from the outer surface of an afflicted organ into the peritoneum. OC outgrowth formation is poorly understood because there is limited availability of OC cell culture models to examine the behavior of cell assemblies that form outgrowths. Prompted by immunochemical evaluation of extracellular matrix (ECM) components, laminin {gamma}1 and collagens, in human tissues representing untreated and chemotherapy-recovered OC, we developed laminin- and collagen-rich ECM-reconstituted cell culture models amenable to studies of cell clusters that can form outgrowths. We demonstrate that ECM promotes outgrowth formation in fallopian tube non-ciliated epithelial cells (FNE) expressing mutant p53-R175H and various OC cell lines. Outgrowths were initiated by cells that had undergone outward translocation and, upon mechanical detachment, could intercalate into mesothelial cell monolayers. Electron microscopy, optical coherence tomography (OCT), and small amplitude oscillatory shear experiments revealed that high ECM concentration increased ECM fibrous network thickness and led to high shear elasticity in the ECM environment. These physical characteristics were associated with the suppression of outgrowths. A culture environment with low ECM concentration mimicked viscoelasticity of malignant peritoneal fluids (ascites) and supported cell proliferation, cell translocation, and outgrowth formation. These results highlight the importance of ECM microenvironments in modulating OC growth and could provide an additional explanation of why primary and recurrent ovarian tumors form outgrowths that protrude into the peritoneal cavity.

cancer biology↗