This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wong, R. P. C. Articles by Kwok, T. T. Search for Related Content PubMed PubMed Citation Articles by Wong, R. P. C. Articles by Kwok, T. T.

Research Articles: Therapeutics, Targets, and Development

p53-R273H gains new function in induction of drug resistance through down-regulation of procaspase-3

Department of Biochemistry, The Chinese University of Hong Kong, Hong Kong SAR, China

Requests for reprints: Tim Tak Kwok, Department of Biochemistry, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China. Phone: 852-26096380; Fax: 852-26037246. E-mail: kwok2020{at}cuhk.edu.hk

Abstract

Development of drug resistance is one of the major obstacles in cancer chemotherapy. The molecular mechanism leading to drug resistance is still not fully understood. A10A cells, a doxorubicin-resistant subline of human squamous cell carcinoma A431 cells, showed cross-resistance to methotrexate and also resistance to the drug-induced apoptosis. The cells also showed overexpression of a mutated form of p53, p53-R273H (Arg to His at codon 273), and down-regulation of procaspase-3. Knockdown of p53-R273H by p53 small interfering RNA in A431 cells increased procaspase-3 level and sensitized the cells to drug-induced apoptosis. On the other hand, transfection of p53-R273H into p53 null human osteosarcoma Saos-2 cells down-regulated procaspase-3 level and induced resistance to the drug toxicity and drug-induced apoptosis. The results support the idea that p53-R273H may gain new functions in induction of drug resistance and impairment in drug-induced apoptosis through down-regulation of procaspase-3 level. The study sheds new light on the understanding of the gain of function and drug resistance mechanisms associated with mutant p53. [Mol Cancer Ther 2007;6(3):1054–8]

Grant support: Direct grant from The Chinese University of Hong Kong, Hong Kong, China.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Current address for R.P.C. Wong: Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada.

Received 6/ 5/06; revised 11/21/06; accepted 1/30/07.

This article has been cited by other articles:

				A. R. Cuddihy, F. Jalali, C. Coackley, and R. G. Bristow WTp53 induction does not override MTp53 chemoresistance and radioresistance due to gain-of-function in lung cancer cells Mol. Cancer Ther., April 1, 2008; 7(4): 980 - 992. [Abstract] [Full Text] [PDF]

				Y. Li, F. Guessous, S. Kwon, M. Kumar, O. Ibidapo, L. Fuller, E. Johnson, B. Lal, I. Hussaini, Y. Bao, et al. PTEN Has Tumor-Promoting Properties in the Setting of Gain-of-Function p53 Mutations Cancer Res., March 15, 2008; 68(6): 1723 - 1731. [Abstract] [Full Text] [PDF]