Tyrosine kinase inhibitor, methyl 2,5-dihydromethylcinnimate, induces PML nuclear body formation and apoptosis in tumor cells

Naoyuki Komura; Mayako Asakawa; Kazuo Umezawa; Kaoru Segawa

doi:10.1016/j.yexcr.2007.03.032

Tyrosine kinase inhibitor, methyl 2,5-dihydromethylcinnimate, induces PML nuclear body formation and apoptosis in tumor cells

Exp Cell Res. 2007 Aug 1;313(13):2753-65. doi: 10.1016/j.yexcr.2007.03.032. Epub 2007 Apr 1.

Authors

Naoyuki Komura¹, Mayako Asakawa, Kazuo Umezawa, Kaoru Segawa

Affiliation

¹ Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Yokohama, Japan.

PMID: 17585903
DOI: 10.1016/j.yexcr.2007.03.032

Abstract

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.

MeSH terms

Antineoplastic Agents / pharmacology*
Apoptosis
Cell Line, Tumor
Cinnamates / pharmacology*
Humans
Neoplasm Proteins / analysis
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism*
Neoplasms / chemistry
Neoplasms / metabolism*
Nuclear Proteins / analysis
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Promyelocytic Leukemia Protein
Protein Kinase Inhibitors / pharmacology*
Protein-Tyrosine Kinases / antagonists & inhibitors
SUMO-1 Protein / analysis
SUMO-1 Protein / genetics
SUMO-1 Protein / metabolism*
Transcription Factors / analysis
Transcription Factors / genetics
Transcription Factors / metabolism*
Tumor Suppressor Protein p53 / analysis
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism*
Tumor Suppressor Proteins / analysis
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism*

Substances

Antineoplastic Agents
Cinnamates
Neoplasm Proteins
Nuclear Proteins
Promyelocytic Leukemia Protein
Protein Kinase Inhibitors
SUMO-1 Protein
Transcription Factors
Tumor Suppressor Protein p53
Tumor Suppressor Proteins
PML protein, human
methyl 2,5-dihydroxycinnamate
Protein-Tyrosine Kinases