title: Regulation of HPV16 E6 and MCL1 by SF3B1 inhibitor in head and neck cancer cells.
abstract: ABT-737 inhibits the anti-apoptotic proteins B-cell lymphoma 2 (BCL-2) and BCL-X(L). Meayamycin B switches the splicing pattern of myeloid cell leukemia factor 1 (MCL1) pre-mRNA. Specifically, inhibition of splicing factor 3B subunit 1 (SF3B1) with meayamycin B promotes the generation of the proapoptotic, short splicing variant (MCL1-S) and diminishes the antiapoptotic, long variant (MCL1-L). This action was previously associated with the cytotoxicity of meayamycin B in non-small cell lung carcinoma cell lines. ABT-737 induced apoptosis in response to an ablation of MCL1-L by meayamycin B. In this study, we further exploited this synergistic combination in head and neck squamous cell carcinoma (HNSCC), up to 90% of which overexpress MCL1 and BCL-X(L). In a panel of seven HNSCC cell lines, the combination of meayamycin B and ABT-737 rapidly triggered a Bax/Bak-mediated apoptosis that overcame the resistance from HPV16-positive HNSCC against each agent alone. Both RT-PCR and Western blotting showed that meayamycin B up-regulated MCL1-S and down-regulated MCL1-L. Significantly, we discovered that SF3B1 was involved in the splicing of oncogenic HPV16 E6 to produce non-oncogenic HPV16 E6*, indicating that SF3B1 may inhibit HPV16-induced tumorigenesis.
authors.affiliation: Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, Pennsylvania 15260, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Gao
authors.affiliation: University of Pittsburgh Cancer institute, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Sumita
authors.initials: S
authors.lastname: Trivedi
authors.affiliation: University of Pittsburgh Cancer institute, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Ferris
authors.affiliation: Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, Pennsylvania 15260, USA.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Koide
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000633:toxicity; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D004357:Drug Synergism; D006367:HeLa Cells; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000473:pathology / Q000821:virology; D052162:Human papillomavirus 16 / Q000378:metabolism*; D006801:Humans; D009025:Morpholines / Q000633:toxicity; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism*; D009596:Nitrophenols / Q000633:toxicity; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000633:toxicity; D011714:Pyrans / Q000633:toxicity; D034622:RNA Interference; D012326:RNA Splicing / Q000187:drug effects; D000072260:RNA Splicing Factors; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000633:toxicity; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: C501332:ABT-737; D001713:Biphenyl Compounds; C068651:E6 protein, Human papillomavirus type 16; D009025:Morpholines; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D009856:Oncogene Proteins, Viral; D010750:Phosphoproteins; D010879:Piperazines; D011714:Pyrans; D000072260:RNA Splicing Factors; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D017413:Ribonucleoprotein, U2 Small Nuclear; C112491:SF3B1 protein, human; D013449:Sulfonamides; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C585895:meayamycin B; D053148:Caspase 3; D053179:Caspase 7