Project description:Metabolic gene expression analysis to explore ICG-001’s impact on metabolic changes associated with glioma differentiation after disrupting the CBP/β-Catenin interaction by treating patient-derived GBM cell lines PBT147 and PBT030 with ICG-001 (0, 5, or 10 µM) for 24 and 72 h using Nanostring nCounter platform
Project description:Metabolic gene expression analysis to explore ICG-001’s impact on metabolic changes associated with glioma differentiation after disrupting the CBP/β-Catenin interaction by treating patient-derived GBM cell lines PBT147 and PBT030 with ICG-001 (0, 5, or 10 µM) for 24 and 72 h using Nanostring nCounter platform
Project description:This review presents new findings on Wnt signaling in endometrial carcinoma and implications for possible future treatments. The Wnt proteins are essential mediators in cell signaling during vertebrate embryo development. Recent biochemical and genetic studies have provided significant insight into Wnt signaling, in particular in cell cycle regulation, inflammation, and cancer. The role of Wnt signaling is well established in gastrointestinal and breast cancers, but its function in gynecologic cancers, especially in endometrial cancers, has not been well elucidated. Development of a subset of endometrial carcinomas has been attributed to activation of the APC/β-catenin signaling pathway (due to β-catenin mutations) and downregulation of Wnt antagonists by epigenetic silencing. The Wnt pathway also appears to be linked to estrogen and progesterone, and new findings implicate it in mTOR and Hedgehog signaling. Therapeutic interference of Wnt signaling remains a significant challenge. Herein, we discuss the Wnt-activating mechanisms in endometrial cancer and review the current advances and challenges in drug discovery.
Project description:Purpose: The purpose of this study was to analyze the effects of miR-640-SLIT1 axis and the Wnt/β-catenin signaling pathway on radiosensitivity of glioma cells. Methods: Relative expressions of miR-640 and slit guidance ligand 1 (SLIT1) in glioma tissues and glioma cell lines U251 and A172 were detected using RT-qPCR. The cell lines were transfected with si-SLIT1 or miR-640 inhibitor to study the radiosensitivity of glioma cells. We detected cell activity using CCK-8 assay, cell migration using wound healing assay, cell invasion using transwell assay, and apoptosis using caspase-3 assay. Results: SLIT1 was upregulated in glioma tissues and cell lines, and inversely correlated with radiation sensitivity. Its knockdown reduced radioresistance, migration, and invasion, but increased apoptosis in U251 and A17 cells. Loss of miR-640 activity upregulated SLIT1, Wnt, and β-catenin protein expression, whereas it inhibited p-GSK-3β protein levels in U251 and A17 cells. These results suggest that miR-640 mediates the radiosensitivity of glioma cells through SLIT1 and the Wnt/β-catenin signaling pathway. Conclusion: The miR-640-SLIT1 axis that regulates the Wnt/β-catenin signaling pathway is a possible therapeutic option for the effective treatment of glioma in combination with radiotherapy.
Project description:Cancer immunotherapy using tumor-specific monoclonal antibodies presents a novel approach for cancer treatment. A monoclonal antibody TA99 specific for gp75 antigen of melanoma initiates neutrophil recruitment in tumor responsible for cancer therapy. Here, a strategy is reported for hijacking neutrophils in vivo using nanoparticles (NPs) to deliver therapeutics into tumor. In a mouse model of melanoma, it is shown that systemically delivered albumin NPs increase in tumor when TA99 antibody is injected; and the NP tumor accumulation is mediated by neutrophils. After the administration of pyropheophorbide-a loaded albumin NPs and TA99, photodynamic therapy significantly suppresses the tumor growth and increases mouse survival compared with treatment with the NPs or TA99. The study reveals a new avenue to treat cancer by NP hitchhiking of immune systems to enhance delivery of therapeutics into tumor sites.
Project description:Recent evidence suggests that microRNAs (miRNAs) can be released to the extracellular microenvironment and mediate cell-cell communication through exosomes. The aim of this study was to identify exosomal miR-301a (exo-miR-301a) involved in glioblastoma (GBM) radioresistance and reveal the possible mechanisms. The exo-miR-301a specifically secreted by hypoxic GBM cells could transfer to corresponding normoxia-cultured cells and promote radiation resistance. Hypoxic exo-miR-301a directly targeted TCEAL7 genes, which were identified as a tumor suppressor in GBM malignancy and actively repressed its' expression in normoxic glioma cells. Our studies indicated that TCEAL7 negatively regulated the Wnt/β-catenin pathway by blocking β-catenin translocation from cytoplasm to nucleus. Interestingly, we clarified that the Wnt/β-catenin signaling was activated by miR-301a and TCEAL7 mediated the important procession. The exo-miR-301a was involved in the resistance to radiotherapy, and the effects would be reversed by miR-301a inhibition or TCEAL7 overexpression to regulate the Wnt/β-catenin axis. Here we show that exo-miR-301a, which is characteristically expressed and secreted by hypoxic glioma cells, is a potent regulator of Wnt/β-catenin and then depresses radiation sensitivity through targeting anti-oncogene TCEAL7. The newly identified exo-miR-301a/TCEAL7-signaling axis could present a novel target for cellular resistance to cancer therapeutic radiation in GBM patients.
Project description:Wnt/?-catenin signaling is implicated in many physiological processes, including development, tissue homeostasis, and tissue regeneration. In human cancers, Wnt/?-catenin signaling is highly activated, which has led to the development of various Wnt signaling inhibitors for cancer therapies. Nonetheless, the blockade of Wnt signaling causes side effects such as impairment of tissue homeostasis and regeneration. Recently, several studies have identified cancer-specific Wnt signaling regulators. In this review, we discuss the Wnt inhibitors currently being used in clinical trials and suggest how additional cancer-specific regulators could be utilized to treat Wnt signaling-associated cancer.
Project description:Melanoma is the most lethal form of skin cancer, resulting from the malignant transformation of epidermal melanocytes. Recent revolutionary progress in targeted therapy and immunotherapy has prominently improved the treatment outcome, but the survival of melanoma patients remains suboptimal. Ferroptosis is greatly involved in cancer pathogenesis and can execute the outcome of immunotherapy. However, the detailed regulatory mechanisms of melanoma cell ferroptosis remain elusive. Herein, we report that Wnt/β-catenin signaling regulates ferroptosis and melanoma immunotherapy efficacy via the regulation of MITF. First of all, we found that Wnt/β-catenin signaling was prominently suppressed in melanoma cell ferroptosis. Then, we proved that targeting β-catenin exacerbated melanoma cell ferroptosis by promoting the generation of lipid peroxidation both in vitro and in vivo. Subsequent mechanistic studies revealed that MITF mediated the effect of Wnt/β-catenin signaling on melanoma cell ferroptosis, and PGC1α and SCD1 were documented as two main effectors downstream of Wnt/β-catenin-MITF pathway. Ultimately, pharmacological inhibition of β-catenin or MITF increased the efficacy of anti-PD-1 immunotherapy in preclinical xenograft tumor model by promoting ferroptosis. Taken together, Wnt/β-catenin signaling deficiency exacerbates ferroptosis in melanoma via the regulation of MITF. Targeting Wnt/β-catenin-MITF pathway could be a promising strategy to potentiate ferroptosis and increase the efficacy of anti-PD-1 immunotherapy.