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

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.

• Authors: Naoyuki Komura, Mayako Asakawa, Kazuo Umezawa, Kaoru Segawa
• Journal: Experimental cell research (Exp Cell Res) Vol. 313 Issue 13 Pg. 2753-65 (Aug 01 2007) ISSN: 0014-4827 [Print] United States
• PMID: 17585903 (Publication Type: Journal Article)

Chemical References

• 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

Topics

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