RanBP3 Regulates Proliferation, Apoptosis and Chemosensitivity of Chronic Myeloid Leukemia Cells via Mediating SMAD2/3 and ERK1/2 Nuclear Transport.

Qian Li,Zhenglan Huang,Xin Wang,Wenli Feng,Yuhang Peng,Teng Wang,Guoyun Jiang,Ke Mou

doi:10.3389/fonc.2021.698410

Abstract

Abnormal subcellular localization of proteins is an important cause of tumorigenesis and drug resistance. Chromosome region maintenance 1 (CRM1), the nuclear export regulator of most proteins, has been confirmed to be over-expressed in various malignancies and is regarded as an efficient target. But the potential role of the CRM1 cofactor RanBP3 (Ran Binding Protein 3) is left unrevealed in chronic myeloid leukemia (CML). Here, we first detected the level of RanBP3 in CML and found an elevated RanBP3 expression in CML compared with control. Then we used shRNA lentivirus to down-regulated RanBP3 in imatinib sensitive K562 cells and resistant K562/G01 cells and found RanBP3 silencing inhibited cell proliferation by up-regulating p21, induced caspase3-related cell apoptosis, and enhanced the drug sensitivity of IM in vitro. Notably, we observed that RanBP3 silencing restored imatinib sensitivity of K562 cells in NOD/SCID mice. Mechanistically, the nuclear aggregation of SMAD2/3 revealed that tumor suppressor axis (TGF-β)-SMAD2/3-p21 was the anti-proliferation program related to RanBP3 knockdown, and the decrease of cytoplasmic ERK1/2 caused by RanBP3 interference leaded to the down-regulation of anti-apoptosis protein p(Ser112)-BAD, which was the mechanism of increased cell apoptosis and enhanced chemosensitivity to imatinib in CML. In summary, this study revealed the expression and potential role of RanBP3 in CML, suggesting that targeting RanBP3 alone or combined with TKIs could improve the clinical response of CML.

Highlights

Chronic myeloid leukemia (CML) is a malignant proliferative disease originated from a fusion gene bcr-abl, which is produced by the translocation of the abl1 gene in chromosome 9 and the bcr gene in chromosome 22 [1,2,3]
We showed that Ran binding protein 3 (RanBP3) was highly expressed in chronic myeloid leukemia (CML) and regulated cell proliferation, apoptosis, and chemosensitivity of Imatinib mesylate (IM) by mediating the nuclear export of SMAD2/3 and extracellular signal-regulated kinase 1/2 (ERK1/2)
Our findings indicated a crucial role of RanBP3 in CML biology, and targeting RanBP3 alone or combined with tyrosine kinase inhibitor (TKI) could improve the clinical response of CML patients

Summary

Introduction

Chronic myeloid leukemia (CML) is a malignant proliferative disease originated from a fusion gene bcr-abl, which is produced by the translocation of the abl gene in chromosome 9 and the bcr gene in chromosome 22 [1,2,3]. Unlike the C-ABL protein encoded by abl gene, BCR-ABL protein loses its ability of nucleocytoplasmic shuttling, is mainly anchored in the cytoplasm [4, 5], and Effect of RanBP3 on CML continuously activates cytoplasmic STAT5, MAPK-ERK, and PI3K-AKT signals by its high tyrosine kinase activity, resulting in promoted leukemogenesis [6, 7]. Imatinib mesylate (IM), the first-line tyrosine kinase inhibitor (TKI), has been widely applied in the clinical therapy of CML patients with the advantage of effectively improving their prognoses [8, 9]. New TKIs are developed for IM-resistant patients [10, 11]. More investigation is required to develop a cure for CML

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Conclusion