| RRC ID |
81809
|
| Author |
Tsubaki M, Takeda T, Matsuda T, Kimura A, Tanaka R, Nagayoshi S, Hoshida T, Tanabe K, Nishida S.
|
| Title |
Hypoxia-inducible factor 1α inhibitor induces cell death via suppression of BCR-ABL1 and Met expression in BCR-ABL1 tyrosine kinase inhibitor sensitive and resistant chronic myeloid leukemia cells.
|
| Journal |
BMB Rep
|
| Abstract |
Chronic myeloid leukemia (CML) has a markedly improved prognosis with the use of breakpoint cluster region-abelson 1 (BCR-ABL1) tyrosine kinase inhibitors (BCR-ABL1 TKIs). However, approximately 40% of patients are resistant or intolerant to BCR-ABL1 TKIs. Hypoxia-inducible factor 1α (HIF-1α) is a hypoxia response factor that has been reported to be highly expressed in CML patients, making it a therapeutic target for BCR-ABL1 TKI-sensitive CML and BCR-ABL1 TKI-resistant CML. In this study, we examined whether HIF-1α inhibitors induce cell death in CML cells and BCR-ABL1 TKI-resistant CML cells. We found that echinomycin and PX-478 induced cell death in BCR-ABL1 TKIs sensitive and resistant CML cells at similar concentrations while the cell sensitivity was not affected with imatinib or dasatinib in BCR-ABL1 TKIs resistant CML cells. In addition, echinomycin and PX-478 inhibited the c-Jun N-terminal kinase (JNK), Akt, and extracellular-regulated protein kinase 1/2 (ERK1/2) activation via suppression of BCR-ABL1 and Met expression in BCR-ABL1 sensitive and resistant CML cells. Moreover, treatment with HIF-1α siRNA induced cell death by inhibiting BCR-ABL1 and Met expression and activation of JNK, Akt, and ERK1/2 in BCR-ABL1 TKIs sensitive and resistant CML cells. These results indicated that HIF-1α regulates BCR-ABL and Met expression and is involved in cell survival in CML cells, suggesting that HIF-1α inhibitors induce cell death in BCR-ABL1 TKIs sensitive and resistant CML cells and therefore HIF-1α inhibitors are potential candidates for CML treatment. [BMB Reports 2023; 56(2): 78-83].
|
| Volume |
56(2)
|
| Pages |
78-83
|
| Published |
2023-2-1
|
| DOI |
10.5483/BMBRep.2022-0095
|
| PII |
5622
|
| PMID |
36195570
|
| PMC |
PMC9978365
|
| MeSH |
Apoptosis
Cell Death
Drug Resistance, Neoplasm
Echinomycin* / therapeutic use
Fusion Proteins, bcr-abl / genetics
Fusion Proteins, bcr-abl / metabolism
Humans
Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / drug therapy
Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / genetics
Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / metabolism
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins c-akt
Tyrosine Kinase Inhibitors
|
| Resource |
| Human and Animal Cells |
HL60(RCB0041)
U937
Jurkat |
