Activation of CDC 25 phosphatase and CDC 2 kinase involved in GL331-induced apoptosis.
CDC 25 is a dual phosphatase responsible for dephosphorylation and, thus, activation of CDC 2 kinase in G2. Abnormal activation of cyclin B-associated CDC 2 kinase has been implicated in apoptosis induced by cancer chemotherapeutic agents such as paclitaxel (Taxol) and etoposide (VP-16). In this study, we found that the CDC 2 kinase could be transiently activated when nasopharyngeal carcinoma NPC-TW01 cells were treated for 3 h with a new anticancer agent, GL331. GL331 treatment also induced a concomitant increase in CDC 25A phosphatase activity and a reduced level of Tyr-15-phosphorylated CDC 2 in NPC-TW01 cells. Furthermore, subsequent apoptotic DNA fragmentation induced by GL331 could be interrupted by treatment of the cells with the cyclin B1-specific antisense oligonucleotides, suggesting that abnormal activation of cyclin B1-associated CDC 2 kinase and CDC 25A phosphatase was involved in GL331-induced apoptosis. Raf-1 has been shown to associate with CDC 25A and, thus, to stimulate its phosphatase activity. Our results revealed that GL331 could facilitate the association of CDC 25A with Raf-1, resulting in the cascade of CDC 25A phosphatase activation and CDC 2 kinase activation, as well as related signaling pathways, and ultimately causing apoptosis in cancer cells.
Huang
T S
TS
Cancer Research Division, National Health Research Institutes, Veterans General Hospital-Taipei, Taiwan, Republic of China. tshuang@gate.sinica.edu.tw
Shu
C H
CH
Yang
W K
WK
Whang-Peng
J
J
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D016203:CDC2 Protein Kinase / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000187:drug effects*; D004789:Enzyme Activation; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000187:drug effects*; D011034:Podophyllotoxin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D020687:cdc25 Phosphatases
D000972:Antineoplastic Agents, Phytogenic; D018797:Cell Cycle Proteins; D016376:Oligonucleotides, Antisense; D016203:CDC2 Protein Kinase; D010749:Phosphoprotein Phosphatases; D020687:cdc25 Phosphatases; D011034:Podophyllotoxin