Overexpression of PTEN increases sensitivity to SN-38, an active metabolite of the topoisomerase I inhibitor irinotecan, in ovarian cancer cells

Purpose: PTEN is a tumor suppressor gene that was identified on chromosome 40q23. In addition to its original function as a tumor suppressor, this gene product was recently reported to enhance the sensitivity of cancer cells to anticancer agents. It is for the purpose of this study to investigate its function and the mechanisms by which PTEN enhances the sensitivity of ovarian cancer to antitumor agents. Experimental Design: PTEN cDNA was introduced into the ovarian cancer cell line SHIN-3 and a high-expression cell line (SHIN-3/PTEN) was established. This cell line and a control were further analyzed. Results: SHIN-3 cells did not carry any mutations in its genome after sequencing. In vitro examination of sensitivity to anticancer agents showed that the 50% growth -inhibitory concentration value for irinotecan metabolite (SN-38) in SHIN-3/PTEN was 800 nM, a 6.6-fold higher sensitivity compared with that of the control (5300 nM). There were no differences in sensitivity to cisplatin, paclitaxel, or gemcitabine between SHIN-3/PTEN and the controls. The percentage of apoptotic cells in SHIN-3/PTEN was 16.6 +/- 0.7% 24 h after addition of SN-38, a significant increase over controls (8.6 +/- 0.9%; P < 0.01). Lower topoisomerase I activity was observed in SHIN-3/PTEN, compared with controls. Conclusions: These results indicate that high PTEN expression enhances the sensitivity, of ovarian cancer cells to irinotecan and the induction of apoptosis and the suppression of topoisomerase I activity in cancer cells are suggested as possible mechanisms attributable to high PTEN expression.