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Epidemiological and clinical evidence have extensively documented the role of obesity in the development of endometrial cancer. However, the effect of fatty acids on cell growth in endometrial cancer has not been widely studied. Here, we reported that palmitic acid significantly inhibited cell proliferation of endometrial cancer cells and primary cultures of endometrial cancer and reduced tumor growth in a transgenic mouse model of endometrial cancer, in parallel with increased cellular stress and apoptosis and decreased cellular adhesion and invasion. Inhibition of cellular stress by N-acetyl-L-cysteine effectively reversed the effects of palmitic acid on cell proliferation, apoptosis, and invasive capacity in endometrial cancer cells. Palmitic acid increased the intracellular formation of lipid droplets in a time- and dose-dependent manner. Depletion of lipid droplets by blocking DGAT1 and DGAT2 effectively increased the ability of palmitic acid to inhibit cell proliferation and induce cleaved caspase 3 activity. Collectively, this study provides new insight into the effect of palmitic acid on cell proliferation and invasion and the formation of lipid droplets that may have potential clinical relevance in the treatment of obesity-driven endometrial cancer. [ABSTRACT FROM AUTHOR]

Porous g-C3N4 composed of nanosheets (p-gCN-NS) was synthesized through firstly grinding the hydrochloric acid-treated melamine with ammonium chloride (NH4Cl) and then calcining the mixture at 550° C for 2 h. The photocatalytic properties were determined by degrading Rhodamine B (RhB) and tetracycline (TC) aqueous solution (10 mg/L, 100 mL). Results show that the crystallinity, size and thickness of g-C3N4 in p-gCN-NS reduced dramatically compared with those in g-C3N4 sample synthesized without the addition of NH4Cl (gCN). Specific surface area of p-gCN-NS was 63.65 m2·g−1, which was 6.7 times that of gCN. After photocatalysis for 50 min, the degradation rate of RhB achieved 99.32% by p-gCN-NS (100 mg), whose reaction rate constant (k = 0.09317 min−1) was 10.6 times higher than that of gCN. p-gCN-NS also exhibited excellent photocatalytic activity for degrading colorless tetracycline aqueous solution. The significant improvement of photocatalytic performance can be credited to the reduced sized and thickness of g-C3N4, higher specific surface area and pore structure, as well as the weakened recombination rate of photogenerated electron–hole pairs in p-gCN-NS. This work provides a feasible and facile method for synthesis porous g-C3N4 composed of nanosheets with excellent photocatalytic performance. [ABSTRACT FROM AUTHOR]

Proinflammatory cytokines, elevated during inflammation caused by infection and/or autoimmune disorders, result in reduced clearance of drugs eliminated primarily by cytochrome P450 enzymes (CYPs). However, the effect of cytokines on hepatic drug transporter expression or activity has not been well-studied. Here, using plated human hepatocytes (PHHs; n = 3 lots), we investigated the effect of interleukin (IL)-6, IL-1 β , tumor necrosis factor- α (TNF- α ), and interferon-γ (IFN-γ), on the mRNA expression and activity of hepatic drug transporters. PHHs were incubated for 72 hours at their pathophysiologically relevant plasma concentrations, both individually (0.01, 0.1, 1, 10 ng/ml) or as a cocktail (i.e., when each was combined at 0.1 or 1 ng/ml). Following cytokine cocktail exposure (1 ng/ml), significant downregulation of mRNA expression of organic anion transporting polypeptide 1B1 (OATP1B1), OATP1B3, sodium/taurocholate cotransporting polypeptide (NTCP), breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), multidrug and toxin extrusion protein 1, multidrug resistance proteins (MRP) 2, 3, and 4 was observed. While the mRNA expression of organic anion transporter (OAT) 2 and organic cation transporter (OCT) 1 was downregulated in two lots, it was upregulated in one lot. In agreement (mostly), the 1 ng/ml cytokine cocktail reduced OATP1B1/3, OATP2B1, OAT2, OCT1, and NTCP activity by 75%, 44%, 82%, 47%, and 80%, respectively. Interestingly, upregulation of OAT2 and OCT1 mRNA in one donor did not translate into the same directional change in activity. Although significant interlot variability was observed, in general, the above effects, using individual cytokines, could be attributed to IL-1 β , TNF- α , and IFN-γ. SIGNIFICANCE STATEMENT: To date, this is the first comprehensive study to investigate the effect of four major proinflammatory cytokines, both individually and as a cocktail, on the mRNA expression and activity of human hepatic drug transporters. The data obtained can be used in the future to predict transporter-mediated drug clearance changes during inflammation through physiologically based pharmacokinetic modeling and simulation., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Emerging evidence has provided considerable insights into the integral function of reprogramming fatty acid metabolism in the carcinogenesis and progression of endometrial cancer. Linoleic acid, an essential fatty acid with the highest consumption in the Western diet regimen, has shown pro-tumorigenic or anti-tumorigenic effects on tumor cell growth and invasion in multiple types of cancer. However, the biological role of linoleic acid in endometrial cancer remains unclear. In the present study, we aimed to investigate the functional impact of linoleic acid on cell proliferation, invasion, and tumor growth in endometrial cancer cells and in a transgenic mouse model of endometrial cancer. The results showed that Linoleic acid significantly inhibited the proliferation of endometrial cancer cells in a dose-dependent manner. The treatment of HEC-1A and KLE cells with linoleic acid effectively increased intracellular reactive oxygen species (ROS) production, decreased mitochondrial membrane potential, caused cell cycle G1 arrest, and induced intrinsic and extrinsic apoptosis pathways. The anti-invasive ability of linoleic acid was found to be associated with the epithelial-mesenchymal transition process in both cell lines, including the decreased expression of N-cadherin, snail, and vimentin. Furthermore, treatment of Lkb1 fl/fl p53 fl/fl transgenic mice with linoleic acid for four weeks significantly reduced the growth of endometrial tumors and decreased the expression of VEGF, vimentin, Ki67, and cyclin D1 in tumor tissues. Our findings demonstrate that linoleic acid exhibits anti-proliferative and anti-invasive activities in endometrial cancer cell lines and the Lkb1 fl/fl p53 fl/fl mouse model of endometrial cancer, thus providing a pre-clinical basis for future dietary interventions with linoleic acid in endometrial cancer.

Ipatasertib (IPAT) is an orally administered, selective protein kinase B (AKT) inhibitor with promising data in solid tumors in both pre-clinical studies and clinical trials. Given that the PI3K/AKT/mTOR pathway is frequently dysregulated in uterine serous carcinoma (USC), we aimed to explore the functional impact of IPAT on anti-tumorigenic activity in USC cell lines and primary cultures of USC. We found that IPAT significantly inhibited cell proliferation and colony formation in a dose-dependent manner in USC cells. Induction of cell cycle arrest and apoptosis was observed in IPAT-treated ARK1 and SPEC-2 cells. Treatment with IPAT resulted in reduced adhesion and invasion of both cell lines with a concomitant decrease in the expression of Snail, Slug, and N-Cadherin. Compared with single-drug treatment, the combination of IPAT and paclitaxel synergistically reduced cell proliferation and increased the activity of cleaved caspase 3 in both cell lines. Additionally, IPAT inhibited growth in four of five primary USC cultures, and three of five primary cultures also exhibited synergistic growth inhibition when paclitaxel and IPAT were combined. These results support that IPAT appears to be a promising targeted agent in the treatment of USC., Competing Interests: None., (AJCR Copyright © 2022.)