Abstract
BackgroundCordyceps militaris (L.) Fr. (C. militaris) exhibits pharmacological activities, including antitumor properties, through the regulation of the nuclear factor kappa B (NF-κB) signaling. Tumor Necrosis Factor (TNF) and TNF-α modulates cell survival and apoptosis through NF- κB signaling. However, the mechanism underlying its mode of action on the NF-κB pathway is unclear.MethodsHere, we analyzed the effect of C. militaris extract (CME) on the proliferation of ovarian cancer cells by confirming viability, morphological changes, migration assay. Additionally, CME induced apoptosis was determined by apoptosis assay and apoptotic body formation under TEM. The mechanisms of CME were determined through microarray, immunoblotting and immunocytochemistry.ResultsCME reduced the viability of cells in a dose-dependent manner and induced morphological changes. We confirmed the decrease in the migration activity of SKOV-3 cells after treatment with CME and the consequent induction of apoptosis. Immunoblotting results showed that the CME-mediated upregulation of tumor necrosis factor receptor 1 (TNFR1) expression induced apoptosis of SKOV-3 cells via the serial activation of caspases. Moreover, CME negatively modulated NF-κB activation via TNFR expression, suggestive of the activation of the extrinsic apoptotic pathway. The binding of TNF-α to TNFR results in the disassociation of IκB from NF-κB and the subsequent translocation of the active NF-κB to the nucleus. CME clearly suppressed NF-κB translocation induced by interleukin (IL-1β) from the cytosol into the nucleus. The decrease in the expression levels of B cell lymphoma (Bcl)-xL and Bcl-2 led to a marked increase in cell apoptosis.ConclusionThese results suggest that C. militaris inhibited ovarian cancer cell proliferation, survival, and migration, possibly through the coordination between TNF-α/TNFR1 signaling and NF-κB activation. Taken together, our findings provide a new insight into a novel treatment strategy for ovarian cancer using C. militaris.
Highlights
Cordyceps militaris (L.) Fr. (C. militaris) exhibits pharmacological activities, including antitumor properties, through the regulation of the nuclear factor kappa B (NF-κB) signaling
We show that C. militaris prevented NF-κB activation by upregulating the expression of tumor necrosis factor receptor 1 (TNFR1) and that the subsequent activation of the extrinsic apoptotic process resulted in the induction of cancer cell death
Upregulation of TNFR1 expression by C. militaris extract (CME) induces apoptosis of cells through the suppression of the nuclear translocation of NF-κB To investigate whether the Tumor Necrosis Factor (TNF)-α/Tumor necrosis factor receptor (TNFR)/NF-κB axis is functionally linked to caspase signaling, we examined the effect TNF-α/TNFR on NF-κB activation
Summary
Cordyceps militaris (L.) Fr. (C. militaris) exhibits pharmacological activities, including antitumor properties, through the regulation of the nuclear factor kappa B (NF-κB) signaling. (C. militaris) exhibits pharmacological activities, including antitumor properties, through the regulation of the nuclear factor kappa B (NF-κB) signaling. The mechanism underlying its mode of action on the NF-κB pathway is unclear. Standard Treatment for epithelial ovarian cancers (EOCs) is based on a combination of surgery and chemotherapy. The carboplatin/paclitaxel doublet remains the chemotherapy backbone for the initial treatment of ovarian cancer [3]. Resistance against chemotherapeutic agents often develops in ovarian cancer patients, contributing to high recurrence rates. Induction of multidrug resistant and incurable tumor recurrence in the majority of patients after initial good response to standard carboplatin/taxane-based treatment are significant factors contributing to this deadly disease [4]. The detailed molecular mechanism underlining this has not been fully elucidated
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