RRC ID |
60001
|
著者 |
Uchida E, Suwa S, Yoshimoto R, Watanabe K, Kasama T, Miura O, Fukuda T.
|
タイトル |
TOPK is regulated by PP2A and BCR/ABL in leukemia and enhances cell proliferation.
|
ジャーナル |
Int J Oncol
|
Abstract |
Although treatment of chronic myeloid leukemia (CML) has improved with the development of tyrosine kinase inhibitors (TKIs), patients develop fatal blast crisis (BC) whilst receiving TKI treatment. Alternative treatments for cases resistant to TKIs are required. A serine/threonine protein kinase, T‑lymphokine‑activated killer cell‑originated protein kinase (TOPK), is highly expressed in various malignant tumors. Binding of peptides to human leukocyte antigen was assessed via mass spectrometry in K562 CML cells. TOPK expression was assessed in various CML cell lines and in clinical samples obtained from patients with CML using reverse transcription‑quantitative polymerase chain reaction and western blot assays. It was observed that TOPK was expressed abundantly in BCR/ABL‑positive cell lines and at significantly higher levels in CML clinical samples compared with healthy donor samples. Overexpression of BCR/ABL or the presence of its inhibitor imatinib upregulated and downregulated TOPK expression, respectively, indicating that TOPK may be a target of BCR/ABL. TOPK inhibitor OTS514 suppressed proliferation of BCR/ABL‑positive cell lines and colony formation of CD34‑positive cells from patients with CML compared with lymphoma patients without bone marrow involvement. Furthermore, phosphorylation of TOPK was increased by protein phosphatase 2A (PP2A) inhibitor okadaic acid and was decreased in the presence of PP2A activator FTY720 compared with untreated samples. As constitutive BCR/ABL activity and inhibition of PP2A are key mechanisms of CML development, TOPK may be a crucial signaling molecule for this disease. Inhibition of TOPK may control disease status of CML, even in cases resistant to TKIs.
|
巻・号 |
54(5)
|
ページ |
1785-1796
|
公開日 |
2019-5-1
|
DOI |
10.3892/ijo.2019.4740
|
PMID |
30864683
|
MeSH |
Adult
Aged
Aged, 80 and over
Blast Crisis / genetics
Blast Crisis / metabolism*
Cell Line, Tumor
Cell Proliferation / drug effects
Female
Fusion Proteins, bcr-abl / genetics
Fusion Proteins, bcr-abl / metabolism*
Gene Expression Regulation, Neoplastic / drug effects
HLA-A24 Antigen / genetics
HLA-A24 Antigen / metabolism
Humans
Imatinib Mesylate / pharmacology
K562 Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology*
Male
Middle Aged
Mitogen-Activated Protein Kinase Kinases / genetics
Mitogen-Activated Protein Kinase Kinases / metabolism*
Phosphorylation
Protein Phosphatase 2 / genetics
Protein Phosphatase 2 / metabolism*
Quinolones / pharmacology
Thiophenes / pharmacology
Young Adult
|
IF |
3.571
|
引用数 |
2
|
リソース情報 |
ヒト・動物細胞 |
K562 |