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Inhibition of Skp2 Sensitizes Chronic Myeloid Leukemia Cells to Imatinib

Authors Chen X, Huang Z, Wu W, Xia R

Received 10 March 2020

Accepted for publication 13 May 2020

Published 22 June 2020 Volume 2020:12 Pages 4777—4787

DOI https://doi.org/10.2147/CMAR.S253367

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Dr Eileen O'Reilly


Xiaowen Chen, Zhenqi Huang, Wei Wu, Ruixiang Xia

Department of Hematology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, People’s Republic of China

Correspondence: Ruixiang Xia Email xiaruixiang@ahmu.edu.cn

Introduction: Skp2 is an E3 ubiquitin ligase that plays an important role in modulating tumor progression. The mechanisms underlying Skp2 in the promotion of proliferation and its function in the primary resistance to tyrosine kinase inhibitors (TKIs) in human CML remain to be determined. This study aimed to investigate the function of Skp2 in CML progression as well as its effects on TKI sensitivity.
Methods: Expression of Skp2 in leukocytes from patients with CML and normal blood samples was analyzed by qRT-PCR. Cell proliferation was analyzed by EdU incorporation and cell counting assays. Luciferase reporter and chromatin immunoprecipitation assays were used for examination of the effects of CREB on Skp2 expression. The apoptosis in vitro of K562 cells was analyzed by MTT and caspase 3/7 activity assays.
Results: The present study demonstrates that Skp2 was expressed at a higher level in patients with CML compared with healthy donors, and the elevated expression of Skp2 is critical for CML cell proliferation. Mechanistically, Skp2 was transcriptionally upregulated by CREB responsive to the PI3K/Akt signaling pathway. Furthermore, inhibition of Skp2 expression by shRNAs or blocking the PI3K/Akt/CREB pathway greatly enhances the sensitivity of CML cells to Imatinib treatment.
Conclusion: We conclude that the PI3K/Akt/CREB axis regulates the sensitivity of K562 cells to Imatinib via mediating Skp2 expression. The present study revealed an unknown role of Skp2 in CML progression and provided new aspects on the Skp2-modulated TKI sensitivity in CML, contributing to the development of potential therapeutic anticancer drugs.

Keywords: Skp2, PI3K/Akt, CREB, Imatinib

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