Overexpression of PTEN increases sensitivity to SN-38, an active metabolite of the topoisomerase I inhibitor irinotecan, in ovarian cancer cells.
OBJECTIVE
PTEN is a tumor suppressor gene that was identified on chromosome 10q23. 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.


METHODS
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.
Saga
Yasushi
Y
Department of Obstetrics and Gynecology, Jichi Medical School, Yakushiji, Minamikawachi, Tochigi 329-0498, Japan. saga@jichi.ac.jp
Mizukami
Hiroaki
H
Suzuki
Mitsuaki
M
Kohno
Takahiro
T
Urabe
Masashi
M
Ozawa
Keiya
K
Sato
Ikuo
I
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D020128:Inhibitory Concentration 50; D000077146:Irinotecan; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D017422:Sequence Analysis, DNA; D059004:Topoisomerase I Inhibitors; D014162:Transfection; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
D000972:Antineoplastic Agents, Phytogenic; D011518:Proto-Oncogene Proteins; D059004:Topoisomerase I Inhibitors; D025521:Tumor Suppressor Proteins; D000077146:Irinotecan; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin