Induction of G2/M arrest, endoreduplication, and apoptosis by actin depolymerization agent pextenotoxin-2 in human leukemia cells, involving activation of ERK and JNK

Dong-Oh Moon, Mun-Ock Kim, Sang-Hyuck Kang, Kyeong-Jun Lee, Moon-Soo Heo, Kwang-Sik Choi, Yung Hyun Choi, Gi-Young Kim
Biochemical Pharmacology 2008 August 1, 76 (3): 312-21
Pectenotoxin-2 (PTX-2) is a natural compound from marine sponges and has been known to inhibit cytokinesis through the depolymerization of actin filaments. To investigate the role of actin dysfunction by PTX-2 in human leukemia cells, we analyzed the effect of PTX-2 on the cell cycle and apoptosis. Cell cycle analysis showed that the depolymerization of actin with PTX-2 induces G2/M phase arrest at 12 h and endoreduplication at 24 h. Analysis of the cell cycle regulatory proteins demonstrated that PTX-2 increases phosphorylation of cdc25c and decreases the protein levels of cdc2 and cyclin B1. The M phase specific marker protein, phospho-histone 3, was also increased by PTX-2. Furthermore, p21 and CDK2, which are associated with the induction of endoreduplication, were also upregulated. PTX-2 also inhibited the growth of leukemia cells and caused a marked increase in apoptosis, as characterized by annexin-V+ cells and caspase-3 activity. Interestingly, we found that induction of G2/M phase arrest, endoreduplication, and apoptosis by PTX-2 is regulated by the extracellular signal-regulated kinase (ERK) and c-jun N-terminal kinase (JNK) pathway. Inhibitors of ERK and JNK more increased the phosphorylation of cdc25c expression at G2/M arrest stages, and decreased p21 and CDK2 expression at endoreduplication stages and Bax expression at apoptotic stages in the presence of PTX-2. These molecular mechanisms provide that PTX-2 induces G2/M phase arrest, endoreduplication, and apoptosis through the ERK and JNK signal pathway via actin depolymerization.

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