https://scholars.lib.ntu.edu.tw/handle/123456789/597278
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.author | Toh Y.-M. | en_US |
dc.contributor.author | TSAI-KUN LI | en_US |
dc.date.accessioned | 2022-03-14T12:48:22Z | - |
dc.date.available | 2022-03-14T12:48:22Z | - |
dc.date.issued | 2011 | - |
dc.identifier.issn | 1078-0432 | - |
dc.identifier.uri | https://www.scopus.com/inward/record.uri?eid=2-s2.0-79960992402&doi=10.1158%2f1078-0432.CCR-11-0235&partnerID=40&md5=ed0f82136a94c212776b31e2a75d8376 | - |
dc.identifier.uri | https://scholars.lib.ntu.edu.tw/handle/123456789/597278 | - |
dc.description.abstract | Purpose: Solid tumors encounter a growth-limiting hypoxic microenvironment as they develop. Hypoxia-inducible factors (HIF) play important roles in hypoxia-associated tumor development and therapeutic resistance. Targeting the HIF pathway (especially HIF-1α) represents a promising cancer treatment strategy. Here, we report a novel class of HIF-1α inhibitors and the possible molecular basis of inhibition. Experimental Design: We analyzed the inhibitory effects of clinically used topoisomerase II (TOP2)-targeting drugs on HIF-1α expression with a primary focus on mitoxantrone. The potential role of TOP2 in mitoxantrone-inhibited HIF-1α expression was studied using pharmacologic inhibition, a knockdown approach, and TOP2 mutant cells. Moreover, involvement of mitoxantrone in proteasome-mediated degradation, transcription, and translation of HIF-1α was examined. Results: The TOP2-targeting mitoxantrone, but neither doxorubicin nor etoposide (VP-16), strongly inhibited HIF-1α expression under hypoxic conditions in a dose- and time-dependent manner. Surprisingly, the mitoxantrone-mediated inhibition of HIF-1α expression was largely independent of two TOP2 isozymes, proteasomal degradation, and transcription. Furthermore, mitoxantrone inhibited HIF-1αexpression and function in a similar fashion as cycloheximide, suggesting that mitoxantrone might inhibit HIF-1α via a blockage at its translation step. In vitro translation experiments using HIF-1α mRNA further confirmed inhibition of HIF-1α translation by mitoxantrone. Interestingly, levels of the polysome-bound HIF-1α and VEGF-A mRNA were elevated and decreased after mitoxantrone treatment, respectively. Conclusions: We have identified the TOP2-targeting compound, mitoxantrone, as an HIF-1α inhibitor possibly through a translation inhibition mechanism, suggesting the possibility of an additional anticancer activity for mitoxantrone. ?2011 AACR. | - |
dc.relation.ispartof | Clinical Cancer Research | - |
dc.subject.classification | [SDGs]SDG3 | - |
dc.subject.other | ametantrone; camptothecin; cycloheximide; DNA topoisomerase (ATP hydrolysing); doxorubicin; etoposide; hypoxia inducible factor 1alpha; messenger RNA; mitoxantrone; proteasome; vasculotropin A; article; cancer cell; concentration response; controlled study; drug targeting; genetic transcription; human; human cell; in vitro study; mutant; priority journal; protein degradation; protein expression; protein function; RNA translation; Antineoplastic Agents; Cell Line, Tumor; Colorectal Neoplasms; DNA Topoisomerases, Type II; Gene Knockout Techniques; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney Neoplasms; Mitoxantrone; Mutation; Proteasome Endopeptidase Complex; Protein Biosynthesis; RNA, Messenger; Signal Transduction | - |
dc.title | Mitoxantrone inhibits HIF-1α expression in a topoisomerase II-independent pathway | en_US |
dc.type | journal article | en |
dc.identifier.doi | 10.1158/1078-0432.CCR-11-0235 | - |
dc.identifier.pmid | 21653687 | - |
dc.identifier.scopus | 2-s2.0-79960992402 | - |
dc.relation.pages | 5026-5037 | - |
dc.relation.journalvolume | 17 | - |
dc.relation.journalissue | 15 | - |
item.openairecristype | http://purl.org/coar/resource_type/c_6501 | - |
item.openairetype | journal article | - |
item.grantfulltext | none | - |
item.cerifentitytype | Publications | - |
item.fulltext | no fulltext | - |
crisitem.author.dept | Microbiology | - |
crisitem.author.dept | Center for Biotechnology | - |
crisitem.author.orcid | 0000-0003-0393-2340 | - |
crisitem.author.parentorg | College of Medicine | - |
crisitem.author.parentorg | Others: University-Level Research Centers | - |
顯示於: | 微生物學科所 |
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