Allergen-Removed Rhus verniciflua Extract Induces Ovarian Cancer Cell Death via JNK Activation

Abstract

Nuclear factor-κB (NF-κB)/Rel transcription factors are best known for their central roles in promoting cell survival in cancer. NF-κB antagonizes tumor necrosis factor (TNF)-α-induced apoptosis through a process involving attenuation of the c-Jun-N-terminal kinase (JNK). However, the role of JNK activation in apoptosis induced by negative regulation of NF-κB is not completely understood. We found that allergen-removed Rhus verniciflua Stokes (aRVS) extract-mediated NF-κB inhibition induces apoptosis in SKOV-3 ovarian cancer cells via the serial activation of caspases and SKOV-3 cells are most specifically suppressed by aRVS. Here, we show that in addition to activating caspases, aRVS extract negatively modulates the TNF-α-mediated IκB/NF-κB pathway to promote JNK activation, which results in apoptosis. When the cytokine TNF-α binds to the TNF receptor, Iκ B dissociates from NF-κB. As a result, the active NF-κB translocates to the nucleus. aRVS extract (0.5 mg/ml) clearly prevented NF-κB from mobilizing to the nucleus, resulting in the upregulation of JNK phosphorylation. This subsequently increased Bax activation, leading to marked aRVS-induced apoptosis, whereas the JNK inhibitor SP600125 in aRVS extract treated SKOV-3 cells strongly inhibited Bax. Bax subfamily proteins induced apoptosis through caspase-3. Thus, these results indicate that aRVS extract contains components that inhibit NF-κB signaling to upregulate JNK activation in ovarian cancer cells and support the potential of aRVS as a therapeutic agent for ovarian cancer.