The combination of PRL-3 inhibitor with sorafenib synergistically promotes AML apoptosis.

Xiaomin Chen,Haihe Wang,Wanhua Cai,Dade Rong,Xiuzhen Tong

doi:10.4149/neo_2021_210301n265

Abstract

Phosphatase of regenerating liver-3 (PRL-3) is recognized as a novel independent crucial driver for AML progression. Thus, the specific inhibitor of PRL-3 would be a potential therapeutic agent to AML in clinics, but there are not enough preclinical applications reported yet. Here we evaluated the cytotoxicity of PRL-3 inhibitor, BR-1, against AML cells ML-1 and MOLM-13. Meanwhile, the effect of BR-1 on the biological characteristics of AML cells and the underlying mechanism was investigated along with the combination of BR-1 and sorafenib on the AML cell viability. Our results show that BR-1 promotes apoptosis by inactivation of the JAK/STAT5 and PI3K/AKT pathways, while inhibits cell proliferation through arresting cell cycle in the S phase. In addition, a combination of BR-1 with sorafenib can further improve the therapeutic effect on AML. Thus, our results demonstrated that BR-1 would be a novel and potent therapeutic agent to AML, and its combination with other anti-AML drugs would be a promising strategy for AML therapy.

Highlights

Acute myeloid leukemia (AML) is a heterogeneous disease
Our results show that BR-1 promotes apoptosis by inactivation of JAK/STAT5 and PI3K/AKT pathways, while inhibits cell proliferation through arresting cell cycle in the S phase
We previously showed that Phosphatase of regenerating liver-3 (PRL-3) is highly expressed in AML patients affect the cell cycle, cell proliferation and apoptosis in AML cell lines, demonstrating PRL-3 as an independent prognostic marker for AML4

Summary

Introduction

Acute myeloid leukemia (AML) is a heterogeneous disease. With the development of tumor genetics and molecular biology, varied molecular characteristics of oncogenes have been disclosed along with applicable prognostic and therapeutic value[1]. Phosphatase of regenerating liver-3 (PRL-3), known as PTP4A3, belongs to the protein tyrosine phosphatase (PTP) family[2] In this family, there are 107 members that modulate the phosphorylation and dephosphorylation of many biologically significant molecules with numerous kinases, which all participates in signaling pathways and play roles in development and tumor progression[3]. Evidence shows that the combination of sorafenib and other anti-tumor drugs can play a synergistic antitumor effect to improve therapy efficacy[11,12,13]. We try to utilize PRL-3 inhibitors BR-1 and sorafenib to characterize their therapeutical effects and the underlying mechanisms in AML, in order to provide a novel and efficient strategy to AML therapy

Materials And Methods

Results

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