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Oncogene overexpression and de novo drug-resistance in human prostate cancer cells
H Yamazaki1, E Schneider, C E Myers
1Biochemical & Molecular Pharmacology Section, NCI, NIH, Bethesda, MD 20892.
Abstract:
We have isolated a variant [PC3(R)] of the human prostate PC3 tumor cell line which showed resistance to several anticancer drugs. Studies to evaluate the mechanisms of resistance to anticancer drugs in the PC3(R) cell line indicated that mdr1 was not overexpressed. Studies also indicated that activities of topo I and topo II were not different in these cell lines, nor was there any difference in the formation of drug-induced KCl-SDS precipitable complexes, indicating that topoisomerases were not involved in the development of resistance in PC3(R) cells. While the activity of glutathione S-transferase and total glutathione levels were also similar in these cell lines, the glutathione peroxidase activity in PC3(R) cells was 5-fold lower than in PC3 cells. Furthermore, proto-oncogene expression for c-jun, c-myc, and H-ras was significantly higher in resistant cells than in sensitive cells, indicating that the amplification of early response genes may play a role in the emergence of de novo resistance in PC3(R) cells.
Insights
A new prostate cancer cell line, PC3(R), exhibits resistance to anticancer drugs. This resistance is linked to lower glutathione peroxidase activity and higher proto-oncogene expression, not mdr1 or topoisomerase alterations.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Prostate cancer remains a significant health concern, with drug resistance limiting treatment efficacy.
- Understanding the molecular mechanisms underlying anticancer drug resistance is crucial for developing more effective therapies.
Purpose of the Study:
- To investigate the mechanisms of acquired resistance to anticancer drugs in a newly isolated variant of the human prostate PC3 tumor cell line, designated PC3(R).
- To identify potential molecular markers associated with de novo drug resistance in prostate cancer.
Main Methods:
- Comparative analysis of drug resistance profiles between PC3 and PC3(R) cell lines.
- Assessment of multidrug resistance gene 1 (mdr1) expression levels.
- Evaluation of topoisomerase I (topo I) and topoisomerase II (topo II) activities.
- Measurement of glutathione S-transferase activity, total glutathione levels, and glutathione peroxidase activity.
- Quantification of proto-oncogene expression, including c-jun, c-myc, and H-ras.
Main Results:
- The PC3(R) cell line demonstrated resistance to multiple anticancer drugs.
- No significant overexpression of mdr1 or differences in topo I and topo II activities were observed between PC3 and PC3(R) cells.
- Glutathione S-transferase activity and total glutathione levels were similar, but glutathione peroxidase activity was 5-fold lower in PC3(R) cells.
- Expression of proto-oncogenes c-jun, c-myc, and H-ras was significantly elevated in the resistant PC3(R) cells compared to the sensitive PC3 cells.
Conclusions:
- Anticancer drug resistance in PC3(R) cells is not mediated by mdr1 overexpression or alterations in topoisomerase activity.
- Reduced glutathione peroxidase activity may contribute to the observed drug resistance.
- Upregulation of early response genes like c-jun, c-myc, and H-ras may play a role in the development of de novo resistance in prostate cancer.