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Thioridazine Enhances P62-Mediated Autophagy and Apoptosis Through Wnt/β-Catenin Signaling Pathway in Glioma Cells.

ABSTRACT: Thioridazine (THD) is a common phenothiazine antipsychotic drug reported to suppress growth in several types of cancer cells. We previously showed that THD acts as an antiglioblastoma and anticancer stem-like cell agent. However, the signaling pathway underlying autophagy and apoptosis induction remains unclear. THD treatment significantly induced autophagy with upregulated AMPK activity and engendered cell death with increased sub-G1 in glioblastoma multiform (GBM) cell lines. Notably, through whole gene expression screening with THD treatment, frizzled (Fzd) proteins, a family of G-protein-coupled receptors, were found, suggesting the participation of Wnt/β-catenin signaling. After THD treatment, Fzd-1 and GSK3β-S9 phosphorylation (inactivated form) was reduced to promote β-catenin degradation, which attenuated P62 inhibition. The autophagy marker LC3-II markedly increased when P62 was released from β-catenin inhibition. Additionally, the P62-dependent caspase-8 activation that induced P53-independent apoptosis was confirmed by inhibiting T-cell factor/β-catenin and autophagy flux. Moreover, treatment with THD combined with temozolomide (TMZ) engendered increased LC3-II expression and caspase-3 activity, indicating promising drug synergism. In conclusion, THD induces autophagy in GBM cells by not only upregulating AMPK activity, but also enhancing P62-mediated autophagy and apoptosis through Wnt/β-catenin signaling. Therefore, THD is a potential alternative therapeutic agent for drug repositioning in GBM.

SUBMITTER: Chu CW

PROVIDER: S-EPMC6386927 | biostudies-literature |

REPOSITORIES: biostudies-literature

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| S-EPMC7496820 | biostudies-literature

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Project description:Gliomas are the main common primary intraparenchymal brain tumor in the central nervous system (CNS), with approximately 7% of the death caused by cancers. In the WHO 2016 classification, molecular dysregulations are part of the definition of particular brain tumor entities for the first time. Nevertheless, the underlying molecular mechanisms remain unclear. Several studies have shown that 75% to 80% of secondary glioblastoma (GBM) showed IDH1 mutations, whereas only 5% of primary GBM have IDH1 mutations. IDH1 mutations lead to better overall survival in gliomas patients. IDH1 mutations are associated with lower stimulation of the HIF-1α a, aerobic glycolysis and angiogenesis. The stimulation of HIF-1α and the process of angiogenesis appears to be activated only when hypoxia occurs in IDH1-mutated gliomas. In contrast, the observed upregulation of the canonical WNT/β-catenin pathway in gliomas is associated with proliferation, invasion, aggressive-ness and angiogenesis.. Molecular pathways of the malignancy process are involved in early stages of WNT/β-catenin pathway-activated-gliomas, and this even under normoxic conditions. IDH1 mutations lead to decreased activity of the WNT/β-catenin pathway and its enzymatic targets. The opposed interplay between IDH1 mutations and the canonical WNT/β-catenin pathway in gliomas could participate in better understanding of the observed evolution of different tumors and could reinforce the glioma classification.

| S-EPMC8229353 | biostudies-literature

LGR5 enhances the osteoblastic differentiation of MC3T3-E1 cells through the Wnt/β-catenin pathway.

Project description:Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) is a Wnt-associated gene that contributes to cell proliferation and self-renewal in various organs. LGR5 is expressed in Ewing sarcoma, and LGR5-overexpressing mesenchymal stem cells promote fracture healing. However, the effects of LGR5 on osteoblastic differentiation remain unclear. The aim of the present study was to explore the function of LGR5 in osteoblastic differentiation. LGR5 was overexpressed or knocked down in the MC3T3-E1 pre-osteoblastic cell line via lentiviral transfection and its function in osteoblastic differentiation was investigated. The mRNA expression levels of the osteoblast differentiation markers alkaline phosphatase (ALP), osteocalcin and collagen type I a1 were determined, and ALP and Alizarin red staining were performed. In addition, the effects of LGR5 modulation on β-catenin and the expression of target genes in the Wnt pathway were investigated. The results revealed that the overexpression of LGR5 promoted osteoblastic differentiation. This was associated with enhancement of the stability of β-catenin and its levels in the cell nucleus, which enabled it to activate Wnt signaling. By contrast, the inhibition of LGR5 decreased the osteogenic capacity of MC3T3-E1 cells. These results indicate that LGR5 is a positive regulator of osteoblastic differentiation, whose effects are mediated through the Wnt/β-catenin signaling pathway. This suggests suggesting that the regulation of LGR5/Wnt/β-catenin signaling has potential as a therapy for osteoporosis.

| S-EPMC8237272 | biostudies-literature

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