Division of Analytical Science, Korea Basic Science Institute, Gwahangno 113, Yuseong-gu, Daejeon, 305-333, Republic of Korea.
Department of Biological Sciences, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
BMC Complement Med Ther. 2020 Jan 13;20(1):1. doi: 10.1186/s12906-019-2780-5.
Cordyceps 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.
Here, 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.
CME 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.
These 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.
蛹虫草（L.）Fr.（C. militaris）通过核因子 kappa B（NF-κB）信号调节表现出药理活性，包括抗肿瘤特性。肿瘤坏死因子（TNF）和 TNF-α 通过 NF-κB 信号调节细胞存活和凋亡。然而，其在 NF-κB 途径中的作用方式的机制尚不清楚。
在这里，我们通过确认活力、形态变化、迁移测定来分析蛹虫草提取物（CME）对卵巢癌细胞增殖的影响。此外，通过凋亡测定和 TEM 下凋亡小体的形成来确定 CME 诱导的细胞凋亡。通过微阵列、免疫印迹和免疫细胞化学确定 CME 的机制。
CME 以剂量依赖性方式降低细胞活力并诱导形态变化。我们证实 CME 处理后 SKOV-3 细胞的迁移活性降低，继而诱导细胞凋亡。免疫印迹结果表明，CME 介导的肿瘤坏死因子受体 1（TNFR1）表达上调通过半胱天冬酶的级联激活诱导 SKOV-3 细胞凋亡。此外，CME 通过 TNFR 表达负调节 NF-κB 激活，提示外源性凋亡途径的激活。TNF-α 与 TNFR 的结合导致 IκB 从 NF-κB 解离，随后活性 NF-κB 易位到细胞核。CME 明显抑制了白细胞介素（IL-1β）从细胞质到细胞核诱导的 NF-κB 易位。B 细胞淋巴瘤（Bcl）-xL 和 Bcl-2 的表达水平降低导致细胞凋亡明显增加。
这些结果表明，蛹虫草抑制卵巢癌细胞增殖、存活和迁移，可能通过 TNF-α/TNFR1 信号和 NF-κB 激活的协调作用。综上所述，我们的研究结果为使用蛹虫草治疗卵巢癌提供了一种新的治疗策略。
