title: Triptolide Induces Cell Killing in Multidrug-Resistant Tumor Cells via CDK7/RPB1 Rather than XPB or p44.
abstract: Multidrug resistance (MDR) is a major cause of tumor treatment failure; therefore, drugs that can avoid this outcome are urgently needed. We studied triptolide, which directly kills MDR tumor cells with a high potency and a broad spectrum of cell death. Triptolide did not inhibit P-glycoprotein (P-gp) drug efflux and reduced P-gp and MDR1 mRNA resulting from transcription inhibition. Transcription factors including c-MYC, SOX-2, OCT-4, and NANOG were not correlated with triptolide-induced cell killing, but RPB1, the largest subunit of RNA polymerase II, was critical in mediating triptolide's inhibition of MDR cells. Triptolide elicited antitumor and anti-MDR activity through a universal mechanism: by activating CDK7 by phosphorylating Thr170 in both parental and MDR cell lines and in SK-OV-3 cells. The CDK7-selective inhibitor BS-181 partially rescued cell killing induced by 72-hour treatment of triptolide, which may be due to partial rescue of RPB1 degradation. We suggest that a precise phosphorylation site on RPB1 (Ser1878) was phosphorylated by CDK7 in response to triptolide. In addition, XPB and p44, two transcription factor TFIIH subunits, did not contribute to triptolide-driven RPB1 degradation and cell killing, although XPB was reported to covalently bind to triptolide. Several clinical trials are underway to test triptolide and its analogues for treating cancer and other diseases, so our data may help expand potential clinical uses of triptolide, as well as offer a compound that overcomes tumor MDR. Future investigations into the primary molecular target(s) of triptolide responsible for RPB1 degradation may suggest novel anti-MDR target(s) for therapeutic development. Mol Cancer Ther; 15(7); 1495-503. ©2016 AACR.
authors.affiliation: Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China.
authors.forename: Jun-Mei
authors.initials: JM
authors.lastname: Yi
authors.affiliation: Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China.
authors.forename: Xia-Juan
authors.initials: XJ
authors.lastname: Huan
authors.affiliation: Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China.
authors.forename: Shan-Shan
authors.initials: SS
authors.lastname: Song
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China.
authors.forename: Hu
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China. zhmiao@simm.ac.cn yqwang@simm.ac.cn.
authors.forename: Ying-Qing
authors.initials: YQ
authors.lastname: Wang
authors.affiliation: Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China. zhmiao@simm.ac.cn yqwang@simm.ac.cn.
authors.forename: Ze-Hong
authors.initials: ZH
authors.lastname: Miao
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D004265:DNA Helicases / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004224:Diterpenes / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004852:Epoxy Compounds / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D010616:Phenanthrenes / Q000494:pharmacology*; D010766:Phosphorylation; D059748:Proteolysis; D012319:RNA Polymerase II / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism*; D014410:Tumor Stem Cell Assay; D000095043:Cyclin-Dependent Kinase-Activating Kinase
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004268:DNA-Binding Proteins; D004224:Diterpenes; D004852:Epoxy Compounds; D010616:Phenanthrenes; D014157:Transcription Factors; C478359:WDR77 protein, human; C072022:XPBC-ERCC-3 protein; C001899:triptolide; D018844:Cyclin-Dependent Kinases; D012319:RNA Polymerase II; D004265:DNA Helicases; D000095043:Cyclin-Dependent Kinase-Activating Kinase; C000722416:CDK7 protein, human