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: Yang Gao, Sumita Trivedi, Robert L Ferris, Kazunori Koide
• Journal: Scientific reports (Sci Rep) Vol. 4 Pg. 6098 (Aug 20 2014) ISSN: 2045-2322 [Electronic] England
• PMID: 25139387 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ABT-737
• Biphenyl Compounds
• E6 protein, Human papillomavirus type 16
• Morpholines
• Myeloid Cell Leukemia Sequence 1 Protein
• Nitrophenols
• Oncogene Proteins, Viral
• Phosphoproteins
• Piperazines
• Pyrans
• RNA Splicing Factors
• RNA, Small Interfering
• Repressor Proteins
• Ribonucleoprotein, U2 Small Nuclear
• SF3B1 protein, human
• Sulfonamides
• bcl-2 Homologous Antagonist-Killer Protein
• bcl-2-Associated X Protein
• bcl-X Protein
• meayamycin B
• Caspase 3
• Caspase 7

Topics

• Apoptosis (drug effects)
• Biphenyl Compounds (toxicity)
• Caspase 3 (metabolism)
• Caspase 7 (metabolism)
• Cell Line, Tumor
• Drug Synergism
• HeLa Cells
• Head and Neck Neoplasms (metabolism, pathology, virology)
• Human papillomavirus 16 (metabolism)
• Humans
• Morpholines (toxicity)
• Myeloid Cell Leukemia Sequence 1 Protein (genetics, metabolism)
• Nitrophenols (toxicity)
• Oncogene Proteins, Viral (genetics, metabolism)
• Phosphoproteins (antagonists & inhibitors, genetics, metabolism)
• Piperazines (toxicity)
• Pyrans (toxicity)
• RNA Interference
• RNA Splicing (drug effects)
• RNA Splicing Factors
• RNA, Small Interfering (metabolism)
• Repressor Proteins (genetics, metabolism)
• Ribonucleoprotein, U2 Small Nuclear (antagonists & inhibitors, genetics, metabolism)
• Sulfonamides (toxicity)
• bcl-2 Homologous Antagonist-Killer Protein (metabolism)
• bcl-2-Associated X Protein (metabolism)
• bcl-X Protein (metabolism)