Journal Article

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

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

2021

Overview

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.

• Publisher: Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
• Subject: 1-Phosphatidylinositol 3-kinase / 13/106 / 13/2 / 13/31 / 13/95 / 38/91 / 631/80/82/23 / 64/60 / 692/699/1541/1990/283/1897 / 82/1 / 82/80 / Acute myeloid leukemia / AKT protein / Animals / Antibodies / Antimetabolites, Antineoplastic - pharmacology / Antineoplastic Combined Chemotherapy Protocols - pharmacology / Biochemistry / Biomedical and Life Sciences / Cell Biology / Cell Culture / Cell cycle / Cell Cycle - drug effects / Cell proliferation / Cell Proliferation - drug effects / Chemotherapy / Cyclin-dependent kinase / Cyclin-dependent kinase 4 / Cyclin-dependent kinases / Cyclin-Dependent Kinases - antagonists & inhibitors / Cyclin-Dependent Kinases - metabolism / Cyclins / Cytarabine - pharmacology / Drug Resistance, Neoplasm / Female / Gene expression / Gene Expression Regulation, Leukemic / Glioma / Glycogen Synthase Kinase 3 - metabolism / Hedgehog protein / HEK293 Cells / Humans / Immunology / Immunoprecipitation / Kinases / Leukemia / Leukemia, Myeloid, Acute - drug therapy / Leukemia, Myeloid, Acute - enzymology / Leukemia, Myeloid, Acute - genetics / Leukemia, Myeloid, Acute - pathology / Life Sciences / Malignancy / Medical prognosis / Mice / Mice, Nude / Myeloid leukemia / Phosphatidylinositol 3-Kinase - metabolism / Piperazines - pharmacology / Protein Kinase Inhibitors - pharmacology / Proto-Oncogene Proteins c-akt - metabolism / Pyridines - pharmacology / Pyrimidines - pharmacology / Signal Transduction / THP-1 Cells / Transcription / Tumor Burden - drug effects / U937 Cells / Xenograft Model Antitumor Assays / Zinc Finger Protein GLI1 - antagonists & inhibitors / Zinc Finger Protein GLI1 - genetics / Zinc Finger Protein GLI1 - metabolism