GLI1 reduces drug sensitivity by regulating cell cycle through PI3K/AKT/GSK3/CDK pathway in acute myeloid leukemia

Zhou, Cheng; Du, Juan; Zhao, Liang; Liu, Wei; Zhao, Tianming; Liang, Hui; Peng, Fang; Zhang, Kaixuan; Zeng, Hui

doi:10.1038/s41419-021-03504-2

Cited by 35 publications

(21 citation statements)

References 36 publications

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“…There have been reports that PI3K signaling pathway is an important non-canonical activator of GLI1 and that targeting the PI3K/AKT pathway via GLI inhibition enhances drug sensitivity (Liang et al, 2017). Conversely, GLI1 reduces drug sensitivity via direct activation of the PI3K pathway in acute myeloid leukemia (Zhou et al, 2021). In our study, in the presence of SHH, XH30 suppressed the hedgehog pathway and partially reversed GLI1 activation.…”

Section: Discussionsupporting

confidence: 49%

The PI3K Inhibitor XH30 Enhances Response to Temozolomide in Drug-Resistant Glioblastoma via the Noncanonical Hedgehog Signaling Pathway

Zhang

Lin

et al. 2021

Front. Pharmacol.

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Glioblastoma multiforme (GBM) is the most common malignant tumor of the central nervous system. Temozolomide (TMZ)–based adjuvant treatment has improved overall survival, but clinical outcomes remain poor; TMZ resistance is one of the main reasons for this. Here, we report a new phosphatidylinositide 3-kinase inhibitor, XH30; this study aimed to assess the antitumor activity of this compound against TMZ-resistant GBM. XH30 inhibited cell proliferation in TMZ-resistant GBM cells (U251/TMZ and T98G) and induced cell cycle arrest in the G1 phase. In an orthotopic mouse model, XH30 suppressed TMZ-resistant tumor growth. XH30 was also shown to enhance TMZ cytotoxicity both in vitro and in vivo. Mechanistically, the synergistic effect of XH30 may be attributed to its repression of the key transcription factor GLI1 via the noncanonical hedgehog signaling pathway. XH30 reversed sonic hedgehog–triggered GLI1 activation and decreased GLI1 activation by insulin-like growth factor 1 via the noncanonical hedgehog signaling pathway. These results indicate that XH30 may represent a novel therapeutic option for TMZ-resistant GBM.

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Section: Discussionsupporting

confidence: 49%

The PI3K Inhibitor XH30 Enhances Response to Temozolomide in Drug-Resistant Glioblastoma via the Noncanonical Hedgehog Signaling Pathway

Zhang

Lin

et al. 2021

Front. Pharmacol.

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“…Moreover, it is significant that these target genes with high-degree are closely related to the PI3K-Akt signaling pathway. Biological studies showed that the dysregulation of the PI3K-Akt signaling pathway in AML may cause the activation of downstream signal molecules, regulate tumor cell proliferation, apoptosis processes, and mediate tumor cell resistance to radiotherapy and chemotherapy [ 47 , 48 ]. Dysregulation of the PI3K-Akt pathway in AML has become the focus of drug research and development.…”

Section: Discussionmentioning

confidence: 99%

Effects of Qinghuang Powder on Acute Myeloid Leukemia Based on Network Pharmacology, Molecular Docking, and In Vitro Experiments

Zeng

Zhang³

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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Qinghuang powder (QHP) is a traditional Chinese herbal medicine. This is a unique formula that is frequently used to treat malignant hematological diseases such as acute myeloid leukemia (AML) in modern clinical practice. An approach of network pharmacology and experimental validation were applied to investigate the pharmacological mechanisms of QHP in AML treatment. First, public databases for target genes known to be associated with AML are searched and compared to the target genes of the active compounds in QHP. Second, AML-associated genes and QHP target genes are compared to identify overlapping enriched genes, and these were used to predict selected target genes that may be implicated in the effects of QHP on AML. Additionally, we conducted functional enrichment analyses, such as gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The significantly enriched pathway associated with potential target proteins was the PI3K-Akt signaling pathway, suggesting that these potential target proteins and pathways may mediate the beneficial biological effects of QHP on AML. All these following genes were found to occur in the compounds-target-pathway networks: AKT1, MAPK1, MAPK3, PIK3CG, CASP3, CASP9, TNF, TGFB1, MAPK8, and TP53. Then, based on the molecular docking studies, it was suggested that the active compound isovitexin can fit into the binding pockets of the top candidate QHP-AML target proteins (PIK3CG). Subsequently, based on the prediction by network pharmacology analysis, both in vitro AML cells and western blot experiments were performed to validate the curative role of QHP. QHP exerted its antitumor activity on AML in vitro, as it inhibits cells proliferation, reduced the expression of Bcl-2 protein, and downregulated the PI3K-Akt signaling pathway. In conclusion, these results revealed that QHP could treat AML via a “multicomponent, multitarget, multipathway” regulatory network. Furthermore, our study also demonstrated that the combination of network pharmacology with the experimental study is effective in discovering and identifying QHP in the treatment of AML and its underlying pharmacological mechanisms.

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“…Glycogen synthase kinase-3 (GSK-3) affects various signaling pathways that are crucial for cellular self-renewal, growth, and survival, including the NF-kB pathway that is critical to AML development [ 44 , 45 , 46 ]. GSK-3 can phosphorylate and stabilize S8, S17, S31, and S43 of NEMO.…”

Section: Discussionmentioning

confidence: 99%

Proteasome Inhibitors Interrupt the Activation of Non-Canonical NF-κB Signaling Pathway and Induce Cell Apoptosis in Cytarabine-Resistant HL60 Cells

Wang

Shih

Shieh

et al. 2021

IJMS

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Over half of older patients with acute myeloid leukemia (AML) do not respond to cytotoxic chemotherapy, and most responders relapse because of drug resistance. Cytarabine is the main drug used for the treatment of AML. Intensive treatment with high-dose cytarabine can increase the overall survival rate and reduce the relapse rate, but it also increases the likelihood of drug-related side effects. To optimize cytarabine treatment, understanding the mechanism underlying cytarabine resistance in leukemia is necessary. In this study, the gene expression profiles of parental HL60 cells and cytarabine-resistant HL60 (R-HL60) cells were compared through gene expression arrays. Then, the differential gene expression between parental HL60 and R-HL60 cells was measured using KEGG software. The expression of numerous genes associated with the nuclear factor κB (NF-κB) signaling pathway changed during the development of cytarabine resistance. Proteasome inhibitors inhibited the activity of non-canonical NF-κB signaling pathway and induced the apoptosis of R-HL60 cells. The study results support the application and possible mechanism of proteasome inhibitors in patients with relapsed or refractory leukemia.

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GLI1 reduces drug sensitivity by regulating cell cycle through PI3K/AKT/GSK3/CDK pathway in acute myeloid leukemia

Cited by 35 publications

References 36 publications

The PI3K Inhibitor XH30 Enhances Response to Temozolomide in Drug-Resistant Glioblastoma via the Noncanonical Hedgehog Signaling Pathway

The PI3K Inhibitor XH30 Enhances Response to Temozolomide in Drug-Resistant Glioblastoma via the Noncanonical Hedgehog Signaling Pathway

Effects of Qinghuang Powder on Acute Myeloid Leukemia Based on Network Pharmacology, Molecular Docking, and In Vitro Experiments

Proteasome Inhibitors Interrupt the Activation of Non-Canonical NF-κB Signaling Pathway and Induce Cell Apoptosis in Cytarabine-Resistant HL60 Cells

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