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p53 gene status modulates the chemosensitivity of non-small cell lung cancer cells
1Chest Department, Veterans General Hospital-Taipei, Taipei, Taiwan, ROC. sllai@vghtpe.gov.tw
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.
Insights
Restoring wild-type p53 in non-small cell lung cancer (NSCLC) cells significantly increased chemosensitivity and apoptosis induction. Conversely, introducing mutant p53 reduced sensitivity, highlighting p53 gene status as a key factor in NSCLC treatment response.
Area of Science:
- Molecular Biology
- Oncology
- Cancer Genetics
Background:
- The p53 tumor suppressor gene plays a critical role in cellular responses to DNA damage.
- Alterations in p53 gene status are common in non-small cell lung cancer (NSCLC) and are associated with treatment resistance.
- Understanding the impact of p53 gene status on chemosensitivity is crucial for developing effective NSCLC therapies.
Purpose of the Study:
- To investigate how p53 gene status influences DNA damage-induced apoptosis and chemosensitivity in NSCLC cells.
- To determine if restoring wild-type p53 function can re-sensitize NSCLC cells to chemotherapeutic agents.
- To assess the effect of introducing mutant p53 into wild-type p53-expressing cells on chemosensitivity and apoptosis.
Main Methods:
- Utilized five NSCLC cell lines with varying p53 gene status (mutant or wild-type).
- Genetically modified cells by transfecting wild-type p53 into mutant p53-carrying cells and vice versa.
- Assessed chemosensitivity to cisplatin, etoposide, and camptothecin, and evaluated DNA damage-induced apoptosis.
Main Results:
- Transfection of wild-type p53 into mutant p53-carrying NSCLC cells (e.g., H1437/wtp53) dramatically increased susceptibility to chemotherapy (7-fold to cisplatin, 21-fold to etoposide, 20-fold to camptothecin).
- Wild-type p53 transfectants exhibited enhanced DNA damage-induced apoptosis, characterized by oligonucleosomal DNA fragmentation.
- Conversely, NSCLC cells expressing introduced mutant p53 showed reduced chemosensitivity and impaired apoptosis induction.
Conclusions:
- Wild-type p53 status is critical for mediating apoptosis and enhancing chemosensitivity in NSCLC.
- Restoring wild-type p53 function can overcome chemoresistance in NSCLC.
- p53 gene status significantly modulates the efficacy of various anticancer agents and the induction of apoptosis in NSCLC.