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GLI1 reduces drug sensitivity by regulating cell cycle through PI3K/AKT/GSK3/CDK pathway in acute myeloid leukemia
- Source :
- Cell Death and Disease, Vol 12, Iss 3, Pp 1-14 (2021), Cell Death & Disease
- Publication Year :
- 2021
- Publisher :
- Nature Publishing Group, 2021.
-
Abstract
- Acute myeloid leukemia (AML) is a hematological malignancy with high incidence and recurrence rates. Gene expression profiling has revealed that transcriptional overexpression of glioma‐associated oncogene 1 (GLI1), a vital gene in the Hedgehog (Hh) signaling pathway, occurs in poor-prognosis AML, and high levels of phosphoinositide-3-kinase, regulatory subunit 1 (PIK3R1) and AKT3 predict shorter overall survival in AML patients. In this study, we discovered that GLI1 overexpression promotes cell proliferation and reduces chemotherapy sensitivity in AML cells while knocking down GLI1 has the opposite effect. Moreover, GLI1 promoted cell cycle progression and led to elevated protein levels of cyclins and cyclin-dependent kinases (CDKs) in AML cells. By luciferase assays and co-immunoprecipitation, we demonstrated that the PI3K/AKT pathway is directly activated by GLI1. GLI1 overexpression significantly accelerates tumor growth and upregulated p-AKT, CDK4, and cyclinD3 in vivo. Notably, the GLI1 inhibitor GANT61 and the CDK4/6 inhibitor PD 0332991 had synergistic effects in promoting Ara-c sensitivity in AML cell lines and patient samples. Collectively, our data demonstrate that GLI1 reduces drug sensitivity by regulating cell cycle through the PI3K/AKT/GSK3/CDK pathway, providing a new perspective for involving GLI1 and CDK4/6 inhibitors in relapsed/refractory (RR) patient treatment.
- Subjects :
- 0301 basic medicine
Cancer Research
Pyridines
THP-1 Cells
Apoptosis
AKT3
Piperazines
Glycogen Synthase Kinase 3
0302 clinical medicine
Antineoplastic Combined Chemotherapy Protocols
biology
integumentary system
Chemistry
Gene Expression Regulation, Leukemic
lcsh:Cytology
Cell Cycle
Cytarabine
Myeloid leukemia
U937 Cells
Cell cycle
Cyclin-Dependent Kinases
Tumor Burden
Leukemia, Myeloid, Acute
030220 oncology & carcinogenesis
Female
Signal Transduction
Antimetabolites, Antineoplastic
Immunology
Mice, Nude
Zinc Finger Protein GLI1
Article
Acute myeloid leukaemia
03 medical and health sciences
Cellular and Molecular Neuroscience
Cyclin-dependent kinase
Animals
Humans
lcsh:QH573-671
Protein kinase B
Protein Kinase Inhibitors
neoplasms
PI3K/AKT/mTOR pathway
Cell Proliferation
Oncogene
Cell growth
Cell Biology
Xenograft Model Antitumor Assays
030104 developmental biology
HEK293 Cells
Pyrimidines
Drug Resistance, Neoplasm
biology.protein
Cancer research
Phosphatidylinositol 3-Kinase
Proto-Oncogene Proteins c-akt
Subjects
Details
- Language :
- English
- ISSN :
- 20414889
- Volume :
- 12
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Cell Death and Disease
- Accession number :
- edsair.doi.dedup.....c1056c30a0e163575687d634245e2afc