Prevention of phosphatidylinositol 3'-kinase-Akt survival signaling pathway during topotecan-induced apoptosis.
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.
Nakashio
A
A
Institute of Molecular and Cellular Biosciences, University of Tokyo, Japan.
Fujita
N
N
Rokudai
S
S
Sato
S
S
Tsuruo
T
T
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D020169:Caspases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D019772:Topotecan / Q000494:pharmacology*; D014162:Transfection; D014407:Tumor Cells, Cultured
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000970:Antineoplastic Agents; D020169:Caspases; D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019772:Topotecan; C494918:AKT1 protein, human; C578562:PDPK1 protein, human