Department of Pulmonary Medicine, Ningbo No. 2 Hospital, Ningbo, Zhejiang 315000, P.R. China.
Department of Emergency Medicine, Ningbo No. 2 Hospital, Ningbo, Zhejiang 315000, P.R. China.
Int J Mol Med. 2019 Jan;43(1):507-516. doi: 10.3892/ijmm.2018.3939. Epub 2018 Oct 18.
Safe, affordable and efficacious agents are urgently required for cancer prevention. Sesamin, a lipid‑soluble lignan from sesame (Sesamum indicum) displays anticancer activities through an unknown mechanism. In the present study, the anticancer activity of sesamin via cyclooxygenase 2 (COX2) was investigated in lung cancer. Quantitative polymerase chain reaction was performed to determine the mRNA expression levels of COX2 in cells, while western blot analysis was used to determine its protein expression levels. Cell proliferation was evaluated by Cell Counting Kit‑8 assay, while apoptosis and cell cycle analyses were conducted by flow cytometry. The results indicated that COX2 expression was upregulated in lung cancer cell lines compared with human normal lung epithelial cell line BEAS‑2B and sesamin was demonstrated to decrease the levels of COX2, inhibit the proliferation of lung cancer cells and promote their apoptosis in a concentration‑dependent manner. Furthermore, decreased COX2 expression potentiated sesamin‑induced apoptosis and G1‑phase arrest, which was correlated with the suppression of gene products associated with cell apoptosis (Bcl‑2 and Bax) and the cell cycle (cyclin E1). In addition, cotreatment with the COX2 inhibitor CAY10404 and sesamin downregulated the expression of downstream molecules of COX2 [including interleukin (IL)1β, IL6 and tumor necrosis factor α] compared with CAY10404 or sesamin alone. Furthermore, cotreatment with sesamin and CAY10404 markedly reduced the levels of phosphorylated protein kinase B (pAkt) and phosoinositide 3 kinase (PI3K) in three lung cancer cell lines. PI3K expression was observed to be under the control of COX2, possibly forming a negative feedback loop. In addition, PI3K depletion induced apoptosis and G1‑phase arrest in A549 cells. These results suggested that sesamin blocked the pAkt‑PI3K signaling pathway by downregulating the expression of COX2, therefore resulting in cell cycle arrest and increased apoptosis in vitro. In conclusion, inhibition of COX2 increased the sensitivity of lung cancer cells to sesamin by modulating pAkt‑PI3K signaling. These results may aid the development of more selective agents to overcome cancer.
需要安全、经济和有效的药物来预防癌症。芝麻素是芝麻油（Sesamum indicum）中的一种脂溶性木脂素，其通过未知机制显示出抗癌活性。在本研究中，通过环氧化酶 2（COX2）研究了芝麻素在肺癌中的抗癌活性。通过定量聚合酶链反应（qPCR）测定细胞中 COX2 的 mRNA 表达水平，通过蛋白质印迹分析（western blot analysis）测定其蛋白表达水平。通过细胞计数试剂盒-8（Cell Counting Kit-8）评估细胞增殖，通过流式细胞术进行细胞凋亡和细胞周期分析。结果表明，与正常人肺上皮细胞系 BEAS-2B 相比，COX2 在肺癌细胞系中表达上调，芝麻素可降低 COX2 水平，抑制肺癌细胞增殖并促进其凋亡，呈浓度依赖性。此外，降低 COX2 表达增强了芝麻素诱导的凋亡和 G1 期阻滞，这与抑制与细胞凋亡（Bcl-2 和 Bax）和细胞周期（cyclin E1）相关的基因产物相关。此外，与 COX2 抑制剂 CAY10404 联合使用可下调 CO2 下游分子（包括白细胞介素（IL）1β、IL6 和肿瘤坏死因子α）的表达，与单独使用 CAY10404 或芝麻素相比。此外，与芝麻素和 CAY10404 联合使用可显著降低三种肺癌细胞系中磷酸化蛋白激酶 B（pAkt）和磷酸肌醇 3 激酶（PI3K）的水平。发现 PI3K 表达受 COX2 控制，可能形成负反馈回路。此外，PI3K 耗竭诱导 A549 细胞凋亡和 G1 期阻滞。这些结果表明，芝麻素通过下调 COX2 的表达阻断了 pAkt-PI3K 信号通路，从而导致体外细胞周期停滞和凋亡增加。总之，抑制 COX2 通过调节 pAkt-PI3K 信号增加了肺癌细胞对芝麻素的敏感性。这些结果可能有助于开发更具选择性的药物来克服癌症。
