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
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Chronic myeloid leukemia (CML) has a markedly improvedprognosis 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 intolerantto BCR-ABL1 TKIs. Hypoxia-inducible factor 1α (HIF-1α) is ahypoxia response factor that has been reported to be highlyexpressed in CML patients, making it a therapeutic target forBCR-ABL1 TKI-sensitive CML and BCR-ABL1 TKI-resistant CML. In this study, we examined whether HIF-1α inhibitors inducecell death in CML cells and BCR-ABL1 TKI-resistant CML cells. We found that echinomycin and PX-478 induced cell death inBCR-ABL1 TKIs sensitive and resistant CML cells at similar concentrationswhile the cell sensitivity was not affected with imatinibor dasatinib in BCR-ABL1 TKIs resistant CML cells. In addition,echinomycin and PX-478 inhibited the c-Jun N-terminalkinase (JNK), Akt, and extracellular-regulated protein kinase 1/2(ERK1/2) activation via suppression of BCR-ABL1 and Met expressionin BCR-ABL1 sensitive and resistant CML cells. Moreover,treatment with HIF-1α siRNA induced cell death by inhibitingBCR-ABL1 and Met expression and activation of JNK,Akt, and ERK1/2 in BCR-ABL1 TKIs sensitive and resistant CMLcells. These results indicated that HIF-1α regulates BCR-ABL andMet expression and is involved in cell survival in CML cells,suggesting that HIF-1α inhibitors induce cell death in BCR-ABL1TKIs sensitive and resistant CML cells and therefore HIF-1α inhibitorsare potential candidates for CML treatment.
Abstract
Chronic myeloid leukemia (CML) has a markedly improvedprognosis 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 intolerantto BCR-ABL1 TKIs. Hypoxia-inducible factor 1α (HIF-1α) is ahypoxia response factor that has been reported to be highlyexpressed in CML patients, making it a therapeutic target forBCR-ABL1 TKI-sensitive CML and BCR-ABL1 TKI-resistant CML. In this study, we examined whether HIF-1α inhibitors inducecell death in CML cells and BCR-ABL1 TKI-resistant CML cells. We found that echinomycin and PX-478 induced cell death inBCR-ABL1 TKIs sensitive and resistant CML cells at similar concentrationswhile the cell sensitivity was not affected with imatinibor dasatinib in BCR-ABL1 TKIs resistant CML cells. In addition,echinomycin and PX-478 inhibited the c-Jun N-terminalkinase (JNK), Akt, and extracellular-regulated protein kinase 1/2(ERK1/2) activation via suppression of BCR-ABL1 and Met expressionin BCR-ABL1 sensitive and resistant CML cells. Moreover,treatment with HIF-1α siRNA induced cell death by inhibitingBCR-ABL1 and Met expression and activation of JNK,Akt, and ERK1/2 in BCR-ABL1 TKIs sensitive and resistant CMLcells. These results indicated that HIF-1α regulates BCR-ABL andMet expression and is involved in cell survival in CML cells,suggesting that HIF-1α inhibitors induce cell death in BCR-ABL1TKIs sensitive and resistant CML cells and therefore HIF-1α inhibitorsare potential candidates for CML treatment.
참고문헌 (22)
- Roskoski R Jr, "Targeting BCR-Abl in the treatment of Philadelphia-chromosome positive chronic myelogenous leukemia", Pharmacol Res, 178, pp.106156~ (2022)
- Steelman LS, "JAK", STAT, Raf, ERK, PI3K, pp.Akt and BCR-ABL in cell cycle progression and leukemogenesis, Leukemia[DOI]
- Hochhaus A, "European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia", Leukemia, 34, pp.966~984 (2020)
- García-Gutiérrez V, "Current treatment options for chronic myeloid leukemia patients failing second-generation tyrosine kinase inhibitors", J Clin Med, 9, pp.2251~ (2020)
- Alves R, "Resistance to tyrosine kinase inhibitors in chronic myeloid leukemiafrom molecular mechanisms to clinical relevance", Cancers, 13, pp.4820~ (2021)
- Tsubaki M, "Contributions of MET activation to BCR-ABL1 tyrosine kinase inhibitor resistance in chronic myeloid leukemia cells", Oncotarget, 8, pp.38717~38730 (2017)
- Chen H, "HIF-α Promotes chronic myelogenous leukemia cell proliferation by upregulating p21 expression", Cell Biochem Biophys, 72, pp.179~183 (2015)
- Ng KP, "Physiologic hypoxia promotes maintenance of CML stem cells despite effective BCR-ABL1 inhibition", Blood, 123, pp.3316~3326 (2014)
- Pezzuto A, "Role of HIF-1 in cancer progression : novel insights. A review", Curr Mol Med, 18, pp.343~351 (2018)
- Mahdi A, "Challenges facing antiangiogenesis therapy : the significant role of hypoxia-inducible factor and MET in development of resistance to anti-vascular endothelial growth factor-targeted therapies", J Cell Physiol, 234, pp.5655~5663 (2019)
- Organ SL, "An overview of the c-MET signaling pathway", Ther Adv Med Oncol, 3, pp.S7~ (2011)
- Li S, "Fumarate hydratase deficiency induces chronic myeloid leukemia progression", Transl Cancer Res, 8, pp.592~602 (2019)
- Zhao F, "Imatinib resistance associated with BCR-ABL upregulation is dependent on HIF-1alpha-induced metabolic reprograming", Oncogene, 29, pp.2962~2972 (2010)
- Lu T, "Up-regulation of hypoxia-inducible factor antisense as a novel approach to treat ovarian cancer", Theranostics, 10, pp.6959~6976 (2020)
- Dong L, "Arylsulfonamide 64B inhibits hypoxia", HIF-induced expression of c-Met and CXCR4 and reduces primary tumor growth and metastasis of uveal melanoma, 2019, pp.25, 2206~2218
- Boissinot M, "The hepatocyte growth factor(HGF)", Met axis : a neglected target in the treatment of chronic myeloproliferative neoplasms?, 2014, pp.6, 1631~1669
- Singh P, "Combating TKI resistance in CML by inhibiting the PI3K", Akt, Med Oncol, pp.2021, 38[DOI]
- Kawakami S, "Pterostilbene downregulates BCR", ABL and induces apoptosis of T315I-mutated BCR, Sci Rep, pp.2022, 12[DOI]
- Liu Z, "Targeting HSPA8 inhibits proliferation via downregulating BCR-ABL and enhances chemosensitivity in imatinib-resistant chronic myeloid leukemia cells", Exp Cell Res, 405, pp.112708~ (2021)
- Tsubaki M, "Overactivation of Akt contributes to MEK inhibitor primary and acquired resistance in colorectal cancer cells", Cancers, 11, pp.1866~ (2019)
- Tsubaki M, "The MIP-1αautocrine loop contributes to decreased sensitivity to anticancer drugs", J Cell Physiol, 233, pp.4258~4271 (2018)
- Tsubaki M, "Overexpression of HIF-1α contributes to melphalan resistance in multiple myeloma cells by activation of ERK1", 2, Akt, and NF-κB, 2019, pp.99, 72~84