Tyrosine kinase inhibitor, methyl 2,5-dihydromethylcinnimate, induces PML nuclear body formation and apoptosis in tumor cells.
Promyelocytic leukemia (PML) nuclear bodies (PML-NBs) are the nuclear structure consisting of various proteins such as PML, SUMO-1, and p53. PML-NBs are implicated in the regulation of tumor suppression, antiviral responses, and apoptosis. In this study, we searched for bioactive metabolites that would promote the formation of PML-NBs in tumor cells. As a result, methyl 2,5-dihydromethylcinnimate (2,5-MeC), a tyrosine kinase inhibitor, enhanced expression and/or stability of PML proteins and induced PML-NB formation in p53 null H1299 cells established from non-small cell lung cancer (NSCLC) and wild-type p53-expressing U2OS cells derived from osteosarcoma. Furthermore, it enhanced apoptosis by exogenously expressed wild type p53 and the expression of p53-responsive genes, such as PUMA and p21, in H1299 cells. 2,5-MeC also activated endogenous p53 and induced apoptosis in U2OS cells. The results suggest that 2,5-MeC is likely to be a promising candidate drug for the clinical treatment of terminal cancer-expressing wild-type p53.
Komura
Naoyuki
N
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Yokohama, Japan.
Asakawa
Mayako
M
Umezawa
Kazuo
K
Segawa
Kaoru
K
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D002934:Cinnamates / Q000494:pharmacology*; D006801:Humans; D009363:Neoplasm Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000737:chemistry / Q000378:metabolism*; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000071156:Promyelocytic Leukemia Protein; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D025842:SUMO-1 Protein / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D002934:Cinnamates; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D047428:Protein Kinase Inhibitors; D025842:SUMO-1 Protein; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; C067472:methyl 2,5-dihydroxycinnamate; D011505:Protein-Tyrosine Kinases