2,338 research outputs found
Development of Dual-Pathway Inhibitors of Raf/MEK/ERK and PI3K/Akt Signaling Pathways.
In the present study, we designed a new chemical template that contains an oxindole moiety as potential dual-pathway inhibitors of the Raf/MEK/ERK and PI3K/Akt signaling pathways. The design hypothesis is to evaluate whether the oxindole ring system will approximately orient functional groups in a similar manner to the thiazolidinedione moiety, and thus maintain biological activity as dual-pathway inhibitors of the Raf/MEK/ERK and PI3K/Akt signaling pathways. Furthermore, the oxindole ring will provide the flexibility to allow the introduction of various substituents on the oxindole moiety, thereby facilitating comprehensive SAR studies to further explore the biological activity
PTHrP treatment of colon cancer cells promotes tumor associated-angiogenesis by the effect of VEGF
We showed that Parathyroid Hormone-related Peptide (PTHrP) induces proliferation, migration, survival and chemoresistance via MAPKs and PI3K/AKT pathways in colorectal cancer (CRC) cells. The objective of this study was to investigate if PTHrP is also involved in tumor angiogenesis. PTHrP increased VEGF expression and the number of structures with characteristics of neoformed vessels in xenografts tumor. Also, PTHrP increased mRNA levels of VEGF, HIF-1α and MMP-9 via ERK1/2 and PI3K/Akt pathways in Caco-2 and HCT116 cells. Tumor conditioned media (TCMs) from both cell lines treated with PTHrP increases the number of cells, the migration and the tube formation in the endothelial HMEC-1 cells, whereas the neutralizing antibody against VEGF diminished this response. In contrast, PTHrP by direct treatment only increased ERK1/2 phosphorylation and the HMEC-1 cells number. These results provide the first evidence related to the mode of action of PTHrP that leads to its proangiogenic effects in the CRC.Fil: Calvo, Natalia Graciela. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - BahĂa Blanca. Instituto de Ciencias BiolĂłgicas y BiomĂ©dicas del Sur. Universidad Nacional del Sur. Departamento de BiologĂa, BioquĂmica y Farmacia. Instituto de Ciencias BiolĂłgicas y BiomĂ©dicas del Sur; ArgentinaFil: Carriere, Pedro Matias. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - BahĂa Blanca. Instituto de Ciencias BiolĂłgicas y BiomĂ©dicas del Sur. Universidad Nacional del Sur. Departamento de BiologĂa, BioquĂmica y Farmacia. Instituto de Ciencias BiolĂłgicas y BiomĂ©dicas del Sur; ArgentinaFil: MartĂn, MarĂa Julia. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - BahĂa Blanca. Instituto de Ciencias BiolĂłgicas y BiomĂ©dicas del Sur. Universidad Nacional del Sur. Departamento de BiologĂa, BioquĂmica y Farmacia. Instituto de Ciencias BiolĂłgicas y BiomĂ©dicas del Sur; ArgentinaFil: Gigola, Graciela. Universidad Nacional del Sur. Departamento de BiologĂa, BioquĂmica y Farmacia; ArgentinaFil: Gentili, Claudia Rosana. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - BahĂa Blanca. Instituto de Ciencias BiolĂłgicas y BiomĂ©dicas del Sur. Universidad Nacional del Sur. Departamento de BiologĂa, BioquĂmica y Farmacia. Instituto de Ciencias BiolĂłgicas y BiomĂ©dicas del Sur; Argentin
Pi3k/pten/akt signaling pathways in germ cell development and their involvement in germ cell tumors and ovarian dysfunctions
Several studies indicate that the PI3K/PTEN/AKT signaling pathways are critical regulators of ovarian function including the formation of the germ cell precursors, termed primordial germ cells, and the follicular pool maintenance. This article reviews the current state of knowledge of the functional role of the PI3K/PTEN/AKT pathways during primordial germ cell development and the dynamics of the ovarian primordial follicle reserve and how dysregulation of these signaling pathways may contribute to the development of some types of germ cell tumors and ovarian dysfunctions
Lewis y Regulate Cell Cycle Related Factors in Ovarian Carcinoma Cell RMG-I in Vitro via ERK and Akt Signaling Pathways
Abstract: Objective: To investigate the effect of Lewis y overexpression on the expression of proliferation-related factors in ovarian cancer cells. Methods: mRNA levels of cyclins, CDKs, and CKIs were measured in cells before and after transfection with the α1,2-fucosyltransferase gene by real-time PCR, and protein levels of cyclins, CDKs and CKIs were determined in cells before and after gene transfection by Western blot. Results: Lewis y overexpression led to an increase in both mRNA and protein expression levels of cyclin A, cyclin D1 and cyclin E in ovarian cancer cells, decrease in both mRNA and protein expression levels of p16 and p21, and decrease of p27 at only the protein expression level without change in its mRNA level. There were no differences in proteins and the mRNA levels of CDK2, CDK4 and CDK6 before and after gene transfection. Anti-Lewis y antibody, ERK and PI3K pathway inhibitors PD98059 and LY294002 reduced the difference in cyclin and CKI expression caused by Lewis y overexpression. Conclusion: Lewis y regulates the expression of cell cycle-related factors through ERK/MAPK and PI3K/Akt signaling pathways to promote cell proliferation. Int. J. Mol. Sci. 2012, 13 829 Keywords: Lewis(y) antigen; cell cycle; cyclin; cyclin-dependent kinases; cyclin-dependent kinase inhibitor
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A Novel Aptamer LL4A Specifically Targets Vemurafenib-Resistant Melanoma through Binding to the CD63 Protein.
Melanoma is a highly aggressive tumor with a poor prognosis, and half of all melanoma patients harbor BRAF mutations. A BRAF inhibitor, vemurafenib (PLX4032), has been approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) to treat advanced melanoma patients with BRAFV600E mutation. However, the efficacy of vemurafenib is impeded by adaptive resistance in almost all patients. In this study, using a cell-based SELEX (systematic evolution of ligands by exponential enrichment) strategy, we obtained a DNA aptamer (named LL4) with high affinity and specificity against vemurafenib-resistant melanoma cells. Optimized truncated form (LL4A) specifically binds to vemurafenib-resistant melanoma cells with dissociation constants in the nanomolar range and with excellent stability and low toxicity. Meanwhile, fluorescence imaging confirmed that LL4A significantly accumulated in tumors formed by vemurafenib-resistant melanoma cells, but not in control tumors formed by their corresponding parental cells in vivo. Further, a transmembrane protein CD63 was identified as the binding target of aptamer LL4A using a pull-down assay combined with the liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. CD63 formed a supramolecular complex with TIMP1 and β1-integrin, activated the nuclear factor кB (NF-кB) and mitogen-activated protein kinase (MAPK) signaling pathways, and contributed to vemurafenib resistance. Potentially, the aptamer LL4A may be used diagnostically and therapeutically in humans to treat targeted vemurafenib-resistant melanoma
The Oncogenic Signaling Pathways in BRAF-Mutant Melanoma Cells are Modulated by Naphthalene Diimide-Like G-Quadruplex Ligands
Melanoma is the most aggressive and deadly type of skin cancer. Despite the advent of targeted therapies directed against specific oncogene mutations, melanoma remains a tumor that is very difficult to treat, and ultimately remains incurable. In the past two decades, stabilization of the non-canonical nucleic acid G-quadruplex structures within oncogene promoters has stood out as a promising approach to interfere with oncogenic signaling pathways in cancer cells, paving the way toward the development of G-quadruplex ligands as antitumor drugs. Here, we present the synthesis and screening of a library of differently functionalized core-extended naphthalene diimides for their activity against the BRAFV600E-mutant melanoma cell line. The most promising compound was able to stabilize G-quadruplexes that formed in the promoter regions of two target genes relevant to melanoma, KIT and BCL-2. This activity led to the suppression of protein expression and thus to interference with oncogenic signaling pathways involved in BRAF-mutant melanoma cell survival, apoptosis, and resistance to drugs. This G-quadruplex ligand thus represents a suitable candidate for the development of melanoma treatment options based on a new mechanism of action and could reveal particular significance in the context of resistance to targeted therapies of BRAF-mutant melanoma cells
Geraniin inhibits bladder cancer cell growth via regulation of PI3K/AKT signaling pathways
Purpose: The effect of geraniin on human bladder transitional carcinoma was not clear, this study was thus intended to reveal it and reveal the mechanism.
Methods: T24 cells were treated with 5, 10, and 20 ÎĽM of geraniin and the viability and apoptosis of T24 cells were determined using thiazolyl blue tetrazolium bromide (MTT) assay and flow cytometry. The protein expression levels of Cyclin D1, p21, BAL-2, BAX, cleaved caspase-3 and PI3K/AKT pathway were evaluated using western blot.
Results: Geraniin decreased T24 cell viability and induced T24 cell cycle arrest. The proportion of T24 cells in S phase was decreased by geraniin. Besides, geraniin promoted T24 cell apoptosis and regulated PI3K/AKT pathway.
Conclusion: Geraniin appears to regulate bladder cancer cell growth by decreasing the levels of PI3K and AKT phosphorylation. Thus, this agent may be useful in the management of bladder cancer
Keywords: Geraniin, T24 cells, Apoptosis, PI3K/AKT signalin
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