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[Cancer Research 60, 5303-5309, September 15, 2000]
© 2000 American Association for Cancer Research

Tumor Biology

Prevention of Phosphatidylinositol 3'-Kinase-Akt Survival Signaling Pathway during Topotecan-induced Apoptosis1

Ayako Nakashio, Naoya Fujita, Susumu Rokudai, Saori Sato and Takashi Tsuruo2

Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032 [A. N., N. F., S. R., S. S., T. T.]; SmithKline Beecham Seiyaku K. K., Tokyo 102-0075 [A. N.]; and Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 170-8455 [T. T.], Japan

The serine/threonine kinase Akt (also known as protein kinase B) is a downstream effector of phosphatidylinositol-3'-kinase [PI(3)K] that is recognized as the major mediator of survival signals that protect cells from undergoing apoptosis. In the course of examining the target molecules of the topoisomerase I inhibitor topotecan, we found that topotecan treatment promoted Akt dephosphorylation that led to the inactivation of Akt in human lung cancer A549 cells. Transfection of the constitutively active akt cDNA into A549 cells resulted in the reduction of the cytotoxic effect of topotecan, indicating that inhibition of the Akt pathway played an important role in exhibition of topotecan-mediated cytotoxic effects. Further analysis of Akt dephosphorylation revealed that topotecan treatment suppressed upstream kinases of Akt, 3-phosphoinositide-dependent protein kinase 1, and PI(3)K. Overall, the results demonstrate that topotecan exhibited its cytotoxic effects by down-regulating the PI(3)K-Akt survival signaling pathway in addition to inhibiting topoisomerase I.




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