蟲草素 (Cordycepin) (3-脫氧腺苷) 是中藥冬蟲夏草中的主要具有功能成分。研究表明，蟲草素可以調控多種信號通路，誘導與凋亡和/或自噬相關的癌細胞死亡。最近的研究還表明，蟲草素可以增加子宮頸癌細胞對放射線的敏感性，促進細胞死亡。因此，我們假設蟲草素可以分別增強放射敏感性以誘導小鼠萊式腫瘤細胞和正常細胞的凋亡，並且研究其相關機制。結果顯示，在24小時，通過增加蟲草素或放射線 (IR) 單獨處理劑量，會顯著降低MA-10和TM3細胞的存活率。而且，蟲草素與輻射處理組則進一步證明蟲草素與IR具有協同作用，可以更顯著的降低MA-10和TM3細胞的存活率。此外，群落形成測定方法顯示，與單獨處理IR的細胞相比，聯合處理蟲草素和IR會顯著降低細胞存活率，這表明蟲草素可增強MA-10小鼠萊迪希腫瘤細胞的放射敏感性。另外，流式細胞儀檢測結果表明，蟲草素單獨使MA-10細胞產生S phase arrest，合併IR和蟲草素的處理則可誘導MA-10和TM3細胞產生G2 / M phase arrest，而且sub G1 phase 的細胞比例在24小時合併處理IR和蟲草素時，會分別增加至38％和9％，這現象暗示著，蟲草素和IR的處理在兩種類型的細胞中均會誘導細胞死亡。此外，western blotting的結果顯示IR和蟲草素的合併處理會增加MA-10細胞中Cleaved caspase-8 / -9 / -3、PARP、Cytochrome c蛋白的表達和減少Bcl-2蛋白的表達，但是在TM3細胞中不會產生表達。而且，蟲草素和IR會藉由調節MA-10細胞中細胞週期相關蛋白Cyclin E、Cyclin A，CDK4，CDK2和CDK1影響細胞週期，進而誘導細胞週期停滯和細胞死亡。此外，100 µM蟲草素和4 Gy IR處理MA-10細胞24小時可誘導GRP78、p-EIF2α、p-IRE1α 和 CHOP的表達增加促進細胞凋亡。有趣的是，在處理蟲草素24小時後，會增加TM3細胞中LC3，Atg5，Atg12-Atg5和p62的表達，這說明蟲草素可能通過誘導TM3細胞自噬而導致細胞死亡。綜上所述，蟲草素會增加放射線的敏感性，並分別透過誘導MA-10細胞走向凋亡，而TM3細胞則可能透過自噬作用，進而造成細胞死亡。

Cordycepin, a 3-deoxyadenosine, is the predominant functional component of the fungus Cordyceps sinensis, a traditional Chinese medicine. Studies have demonstrated that cordycepin could modulate multiple signaling pathways to induce cancer cell death related to apoptosis and/or autophagy. Recent study has also shown that cordycepin could increase radiosensitivity in cervical cancer cells to promote apoptotic cell death. Hence, we hypothesized that cordycepin could enhance radiosensitivity to induce apoptosis in mouse Leydig tumor and normal cells, respectively, and in the present study with the mechanism investigations. Results showed that cell viabilities among MA-10 and TM3 cells were significantly decreased by increasing dosage of cordycepin or IR alone treatments in 24 hr. Cordycepin combined with radiation treatment further demonstrated synergistic effect reducing cell viability on MA-10 and TM3 cells, respectively. Moreover, clonogenic assay showed that the combined treatment of cordycepin and IR resulted in significantly decrease of survival fractions compared to cells treated with IR alone, indicating that cordycepin could enhance radiosensitivity in MA-10 mouse Leydig tumor cells. In addition, flow cytometry assays showed that cordycepin alone may cause S phase arrest in MA-10 cells, and the combined radiation and cordycepin treatment could induce G2/M phase arrest in MA-10 and TM3 cells, while the percentages of sub G1 phase cell showed 38% and 9% in 24 hr treatments, respectively, implying cordycepin and radiation did induce cell death in both cell types. Moreover, western blotting results showed that combination treatment of radiation and cordycepin increased cleaved caspase-8 /-9 /-3, PARP and Cytochrome c, and decreased Bcl-2 protein expressions in MA-10 cells, but not in TM3 cells. In addition, cordycepin and radiation could affect cell cycle by regulating cell cycle related proteins; Cyclin E, Cyclin A, CDK4, CDK2 and CDK1 to induce cell cycle arrest and cell death in MA-10 cells. Moreover, 100 μM cordycepin and 4 Gy IR for 24 hr could increase the expression of GRP78, p-EIF2α, p-IRE1α and CHOP to promote apoptosis in MA-10 cells. Interestingly, cordycepin in 24 hr treatment increased the expression of LC3, Atg5, Atg12-Atg5 and p62 in TM3 cells, illustrating cordycepin could induce TM3 cell death through autophagy. In summary, cordycepin could enhance radiosensitivity to induce cell death in MA-10 cells through apoptosis and in TM3 cells through autophagy, respectively.

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