Cited 99 times in
AMPK-ULK1-Mediated Autophagy Confers Resistance to BET Inhibitor JQ1 in Acute Myeloid Leukemia Stem Cells
DC Field | Value | Language |
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dc.contributor.author | 김진석 | - |
dc.contributor.author | 민유홍 | - |
dc.contributor.author | 이정연 | - |
dc.contributor.author | 장지은 | - |
dc.contributor.author | 정준원 | - |
dc.date.accessioned | 2018-07-20T07:29:50Z | - |
dc.date.available | 2018-07-20T07:29:50Z | - |
dc.date.issued | 2017 | - |
dc.identifier.issn | 1078-0432 | - |
dc.identifier.uri | https://ir.ymlib.yonsei.ac.kr/handle/22282913/160221 | - |
dc.description.abstract | Purpose: Bromodomain and extraterminal domain (BET) inhibitors are promising epigenetic agents for the treatment of various subsets of acute myeloid leukemia (AML). However, the resistance of leukemia stem cells (LSC) to BET inhibitors remains a major challenge. In this study, we evaluated the mechanisms underlying LSC resistance to the BET inhibitor JQ1.Experimental Design: We evaluated the levels of apoptosis and autophagy induced by JQ1 in LSC-like leukemia cell lines and primary CD34+CD38- leukemic blasts obtained from AML cases with normal karyotype without recurrent mutations.Results: JQ1 effectively induced apoptosis in a concentration-dependent manner in JQ1-sensitive AML cells. However, in JQ1-resistant AML LSCs, JQ1 induced little apoptosis and led to upregulation of beclin-1, increased LC3-II lipidation, formation of autophagosomes, and downregulation of p62/SQSTM1. Inhibition of autophagy by pharmacologic inhibitors or knockdown of beclin-1 using specific siRNA enhanced JQ1-induced apoptosis in resistant cells, indicating that prosurvival autophagy occurred in these cells. Independent of mTOR signaling, activation of the AMPK (pThr172)/ULK1 (pSer555) pathway was found to be associated with JQ1-induced autophagy in resistant cells. AMPK inhibition using the pharmacologic inhibitor compound C or by knockdown of AMPKα suppressed autophagy and promoted JQ1-induced apoptosis in AML LSCs.Conclusions: These findings revealed that prosurvival autophagy was one of the mechanisms involved in the resistance AML LSCs to JQ1. Targeting the AMPK/ULK1 pathway or inhibition of autophagy could be an effective therapeutic strategy for combating resistance to BET inhibitors in AML and other types of cancer. | - |
dc.description.statementOfResponsibility | restriction | - |
dc.language | English | - |
dc.publisher | American Association for Cancer Research | - |
dc.relation.isPartOf | CLINICAL CANCER RESEARCH | - |
dc.rights | CC BY-NC-ND 2.0 KR | - |
dc.rights | https://creativecommons.org/licenses/by-nc-nd/2.0/kr/ | - |
dc.subject.MESH | AMP-Activated Protein Kinases/genetics* | - |
dc.subject.MESH | Apoptosis/drug effects | - |
dc.subject.MESH | Autophagy/drug effects | - |
dc.subject.MESH | Autophagy-Related Protein-1 Homolog/genetics* | - |
dc.subject.MESH | Azepines/administration & dosage* | - |
dc.subject.MESH | Cell Line, Tumor | - |
dc.subject.MESH | Cell Lineage/drug effects | - |
dc.subject.MESH | Drug Resistance, Neoplasm/genetics | - |
dc.subject.MESH | Gene Expression Regulation, Neoplastic/drug effects | - |
dc.subject.MESH | Humans | - |
dc.subject.MESH | Intracellular Signaling Peptides and Proteins/genetics* | - |
dc.subject.MESH | Leukemia, Myeloid, Acute/drug therapy* | - |
dc.subject.MESH | Leukemia, Myeloid, Acute/genetics | - |
dc.subject.MESH | Leukemia, Myeloid, Acute/pathology | - |
dc.subject.MESH | Neoplasm Proteins | - |
dc.subject.MESH | Neoplastic Stem Cells/drug effects | - |
dc.subject.MESH | Proteins/antagonists & inhibitors | - |
dc.subject.MESH | Proteins/genetics | - |
dc.subject.MESH | RNA, Small Interfering | - |
dc.subject.MESH | Signal Transduction/genetics | - |
dc.subject.MESH | Triazoles/administration & dosage* | - |
dc.title | AMPK-ULK1-Mediated Autophagy Confers Resistance to BET Inhibitor JQ1 in Acute Myeloid Leukemia Stem Cells | - |
dc.type | Article | - |
dc.contributor.college | College of Medicine | - |
dc.contributor.department | Dept. of Internal Medicine | - |
dc.contributor.googleauthor | Ji Eun Jang | - |
dc.contributor.googleauthor | Ju-In Eom | - |
dc.contributor.googleauthor | Hoi-Kyung Jeung | - |
dc.contributor.googleauthor | June-Won Cheong | - |
dc.contributor.googleauthor | Jung Yeon Lee | - |
dc.contributor.googleauthor | Jin Seok Kim | - |
dc.contributor.googleauthor | Yoo Hong Min | - |
dc.identifier.doi | 10.1158/1078-0432.CCR-16-1903 | - |
dc.contributor.localId | A01017 | - |
dc.contributor.localId | A01407 | - |
dc.contributor.localId | A03114 | - |
dc.contributor.localId | A03477 | - |
dc.contributor.localId | A03729 | - |
dc.relation.journalcode | J00564 | - |
dc.identifier.pmid | 27864418 | - |
dc.identifier.url | http://clincancerres.aacrjournals.org/content/23/11/2781.long | - |
dc.contributor.alternativeName | Kim, Jin Seok | - |
dc.contributor.alternativeName | Min, Yoo Hong | - |
dc.contributor.alternativeName | Lee, Jung Yoen | - |
dc.contributor.alternativeName | Jang, Ji Eun | - |
dc.contributor.alternativeName | Cheong, June Won | - |
dc.contributor.affiliatedAuthor | Kim, Jin Seok | - |
dc.contributor.affiliatedAuthor | Min, Yoo Hong | - |
dc.contributor.affiliatedAuthor | Lee, Jung Yoen | - |
dc.contributor.affiliatedAuthor | Jang, Ji Eun | - |
dc.contributor.affiliatedAuthor | Cheong, June-Won | - |
dc.citation.volume | 23 | - |
dc.citation.number | 11 | - |
dc.citation.startPage | 2781 | - |
dc.citation.endPage | 2794 | - |
dc.identifier.bibliographicCitation | CLINICAL CANCER RESEARCH, Vol.23(11) : 2781-2794, 2017 | - |
dc.identifier.rimsid | 39077 | - |
dc.type.rims | ART | - |
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