Establishment of ponasterone A-inducible the wild-type p53 protein-expressing clones from HSC-1 cells, cell growth suppression by p53 expression and the suppression mechanism

• Published in: Archives of Dermatological Research 2009-09, Vol.301 (9), p.631-646
• Main Authors: Hori, Makoto, Suzuki, Keiji, Udono, Masako U, Yamauchi, Motohiro, Mine, Mariko, Watanabe, Masami, Kondo, Shigeo, Hozumi, Yutaka
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Carcinoma - therapy; Cell Division - genetics; Cell Line, Tumor; Cellular Senescence; Dermatology; Ecdysterone - analogs & derivatives; Ecdysterone - pharmacology; Feasibility Studies; Gene Expression - drug effects; Genetic Therapy - methods; Genetic Vectors; Humans; Medical sciences; Medicine; Medicine & Public Health; Original Paper; Plasmids; Skin Neoplasms - therapy; Transfection; Tumor Suppressor Protein p53 - biosynthesis; Tumor Suppressor Protein p53 - genetics
• ISSN: 0340-3696; 1432-069X
• DOI: 10.1007/s00403-008-0915-5

Gene therapy for a variety of human cancers containing the mutant p53 (mt-p53) gene has been performed by direct injection of a retroviral or adenoviral vector containing the wild-type p53 (wt-p53) gene. Because many individuals with skin squamous cell carcinoma (SCC) have been shown to carry the p53 gene mutation, these patients are candidates for p53 gene therapy. For this reason, we established ponasterone A-inducible the wild-type p53 (wt-p53) protein-expressing clones by transfecting a ponasterone-inducible vector containing the wt-p53 gene into HSC-1 cells, which harbor the mutated p53 m/w at codon 173 (GTG [rightward arrow] TTG in one allele). Upon the induction of the wt-p53 protein, severe growth suppression was observed. Based on the results of the expression patterns of the p21, p16, RB, BAX and Bcl-2 proteins, as well as on the results of senescence-associated β-galactosidase staining, the suppression was caused by senescence-like growth arrest of the cells. Although it is generally accepted that the suppression of tumor cell growth is caused by p53-induced apoptosis, permanent G1 arrest induced by p53 is also an important part of the growth-suppression mechanism in p53 gene therapy. The present results should expand the possibilities for p53 gene therapy for human skin SCCs containing the mutant p53 gene.