Pectenotoxin-2 abolishes constitutively activated NF-kappaB, leading to suppression of NF-kappaB related gene products and potentiation of apoptosis.
Although pectenotoxin-2 (PTX-2) is known to modify the actin cytoskeleton, very little is known about its apoptosis mechanism. In this study, we investigated whether PTX-2 induces apoptotic effects through suppression of the NF-kappaB signaling pathway in several leukemia cell types. PTX-2 significantly induced growth inhibition and apoptosis in a dose-dependent manner. Treatment with PTX-2 also significantly increased caspase-3 activity and poly (ADP-ribose) polymerase (PARP) cleavage, however caspase-3 inhibitor z-DEVD-fmk significantly inhibited PTX-2-induced cell death. These data suggest that the activation of caspase-3 is associated with PTX-2-induced apoptosis. NF-kappaB has also been shown to inhibit apoptosis in response to chemotherapeutic agents. As examined by the DNA-binding of NF-kappaB activation, we found that PTX-2 suppressed constitutive NF-kappaB activation and determined by p65 and p50 nuclear translocation, and IkappaBalpha degradation through dephosphorylation of Akt. Attenuation of constitutive NF-kappaB activity by pretreatment with pyrrolidine dithiocarbamate (PDTC), an NF-kappaB nuclear translocation inhibitor, induced significantly apoptosis in the presence of PTX-2. In addition, treatment of PTX-2 down-regulated NF-kappaB-dependent gene expression, Cox-2, IAP-1, IAP-2 and XIAP, at the transcriptional and translational level. Taken together, these results suggest that anti-cancer activities induced by PTX-2 may be mediated in part through suppression of constitutive NF-kappaB activity.
Kim
Mun-Ock
MO
Department of Microbiology, College of Natural Sciences, Pusan National University, Busan, Republic of Korea.
Moon
Dong-Oh
DO
Heo
Moon-Soo
MS
Lee
Jae-Dong
JD
Jung
Jee Hyung
JH
Kim
Se-Kwon
SK
Choi
Yung Hyun
YH
Kim
Gi-Young
GY
D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D005663:Furans / Q000494:pharmacology*; D006801:Humans; D018942:Macrolides; D016328:NF-kappa B / Q000378:metabolism* / Q000502:physiology; D011714:Pyrans / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D000095702:Polyether Toxins
D017931:DNA Primers; D005663:Furans; D018942:Macrolides; D016328:NF-kappa B; D011714:Pyrans; C098380:pectenotoxin 2; D000095702:Polyether Toxins