TANK-binding kinase 1 inhibitor GSK8612 enhances daunorubicin sensitivity in acute myeloid leukemia cells via the AKT-CDK2 pathway.

Abstract

PURPOSE:

It has been established in previous studies that TANK-binding kinase 1 (TBK1) is upregulated in malignant tumors and is therefore associated with poor prognosis. However, the role of TBK1 in acute myeloid leukemia (AML) remains unclear. In this study, we investigated the expression levels and the function of TBK1 in AML.

METHODS:

First, TBK1 expression was detected and analyzed using Western blot and qRT-PCR. Then, GSK8612, a novel TBK1 inhibitor, and TBK1-specific siRNA (si-TBK1) were used to inhibit TBK1 function and expression. The effects of TBK1 inhibition on AML were investigated first through a cell counting kit (CCK-8) assay, followed by trypan blue staining to assess cell apoptosis and cell cycle progression in vitro. Finally, the signaling pathway activities in HL-60 and Kasumi-1 cells and patients' mononuclear cells (MNCs) were explored using western blot.

RESULTS:

We found a significantly higher TBK1 expression in AML patients with poor prognoses. GSK8612 successfully inhibited TBK1 expression, resulting in the increased sensitivity of AML cells to daunorubicin. Mechanistically, TBK1 inhibition (by GSK8612 and si-TBK1) regulated cyclin-dependent kinase 2 (CDK2) levels in AML cells via the AKT pathway. Moreover, it was observed that the inhibition of protein kinase B (AKT) activity also resulted in the increased sensitivity of AML cell lines to daunorubicin, validating the relationship between TBK1 and the AKT-CDK2 pathway. Similar results were obtained in MNCs from patients with AML.

CONCLUSION:

TBK1 is a potential prognostic factor for AML, and its inhibition may improve the sensitivity of AML cells to daunorubicin. This regulatory effect is predicted to involve the TBK1-AKT-CDK2 pathway.

• Authors: Siyu Chen, Ming Ni, Tianzhen Hu, Yangguang Gu, Cheng Feng, Chengyun Pan, Siyu Zhang, Shuangshuang Wen, Naiqin Zhao, Weili Wang, Lihong Dai, Jishi Wang
• Journal: American journal of translational research (Am J Transl Res) Vol. 13 Issue 12 Pg. 13640-13653 ( 2021) ISSN: 1943-8141 [Print] United States
• PMID: 35035703 (Publication Type: Journal Article)
• Copyright: AJTR Copyright © 2021.