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.
Highlights
Glioblastoma multiforme (GBM, grade IV astrocytoma) is the most prevalent form of central nervous system (CNS) tumor
To examine whether THD and its analogs exert antitumor effects on glioblastoma multiform (GBM), we used the SRB and clonogenic assays to verify the cytotoxic effect of these drugs on GBM cell lines, U87MG, and GBM840
In GBM 8401 clonogenic assay, the IC50 values of THD analog-1, THD analog-2, and THD were 4.4, 1.8, and 3.5 μM, respectively. These results suggested that cell viability was inhibited in the THD-treated GBM cells
Summary
Glioblastoma multiforme (GBM, grade IV astrocytoma) is the most prevalent form of central nervous system (CNS) tumor. Developing more effective therapeutic strategies, such as drug synergism of TMZ with another compound, is crucial to improve the clinical outcome of GBM treatment. Treatment of GBM cells with TMZ results in autophagy and apoptosis [3,4,5]. Autophagy and apoptosis are crucial self-destructive processes that serve as internal balancing mechanisms to maintain homeostasis in eukaryotic cells. Autophagy may either involve cell death, named type II programmed cell death, or play a prosurvival role as part of an adaptive and detoxifying process in response to sublethal stresses such as starvation, hypoxia, heat shock, and microbial pathogens [6]. P62 is a multifunctional adapter protein, which is implicated in both apoptotic and autophagic processes. P62 acts as the signaling core in orchestrating apoptosis [9]
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