p53 Gene Status Modulates the Chemosensitivity of Non-Small Cell Lung Cancer Cells

Abstract

This study examined the effects of p53 gene status on DNA damage-induced cell death and chemosensitivity to various chemotherapeutic agents in non-small cell lung cancer (NSCLC) cells. A mutant p53 gene was introduced into cells carrying the wild-type p53 gene and also vice versa to introduce the wild-type p53 gene into cells carrying the mutant p53 gene. Chemosensitivity and DNA damage-induced apoptosis in these cells were then examined. This study included five cell lines, NCI-H1437, NCI-H727, NCI-H441 and NCI-H1299 which carry a mutant p53 gene and NCI-H460 which carries a wild-type p53 gene. Mutant p53-carrying cells were transfected with the wild-type p53 gene, while mutant p53 genes were introduced into NCI-H460 cells. These p53 genes were individually mutated at amino acid residues 143, 175, 248 and 273. The representative cell line NCI-H1437 cells transfected with wild-type p53 gene (H1437/wtp53) showed a dramatic increase in susceptibility to three anticancer agents (7-fold to cisplatin, 21-fold to etoposide, and 20-fold to camptothecin) compared to untransfected or neotransfected H1437 cells. An increase in chemosensitivity was also observed in wild-type p53 transfectants of H727, H441, H1299 cells. The results of chemosensitivity were consistent with the observations on apoptotic cell death. H1437/wtp53 cells, but not H1437 parental cells, exhibited a characteristic feature of apoptotic cell death that generated oligonucleosomal-sized DNA fragments. In contrast, loss of chemosensitivity and lack of p53-mediated DNA degradation in response to anticancer agents were observed in H460 cells transfected with mutant p53. These observations suggest that the increase in chemosensitivity was attributable to wild-type p53 mediation of the process of apoptosis. In addition, our results also suggest that p53 gene status modulates the extent of chemosensitivity and the induction of apoptosis by different anticancer agents in NSCLC cells.

Crippling p53 activities via knock-in mutations in mouse models

“…In vitro and in vivo studies show that some mutant p53 proteins have oncogenic potential, called gain of function (Roemer, 1999;Deppert et al, 2000;van Oijen and Slootweg, 2000;Cadwell and Zambetti, 2001). Clinically, patients with some p53 missense mutations have a worse prognosis than patients with deletion of p53, supporting the gainof-function hypothesis (Roemer, 1999;Lai et al, 2000;Powell et al, 2000;Skaug et al, 2000;Iacopetta, 2003). To address mechanisms of gain of function in vivo, two groups have recently characterized knock-in mice with p53 'hot spot' missense mutations Olive et al, 2004).…”

Gain-of-Function Activity of Mutant p53 in Lung Cancer through Up-Regulation of Receptor Protein Tyrosine Kinase Axl

“…9,21,22 It appears that its mutational status determines the efficacy of many of the chemotherapeutic drugs. [22][23][24][25][26] The GOF phenotypes can be partially explained by a dominant-negative effect of mutant p53 on p73 and p63. [27][28][29][30][31] Receptor tyrosine kinases (RTKs) play an important role in the growth and differentiation of normal cells and represent a major class of proto-oncogenes that are involved in the progression and metastasis of cancer.…”

Docosahexaenoic Acid (DHA) Induces P53-Dependent Growth Inhibition in Transformed Colon and Lung Cell Lines Expressing Wildtype P53

“…WiDr, a derivative of the HT-29 colon adenocarcinoma, posses a mutated p53 codon (His273) (Chen et al, 1987;Tamura et al, 1995), while H441 also has a p53 mutation (Lai et al, 2000). Both COLO 205 and A549 have wildtype p53 (Kato et al, 2007;Mukhopadhyay and Roth, 1997).…”