成纖維細胞生長因子 9 (FGF9)是 FGF 家族的成員之一。在睾丸中，FGF9的異常表達會促進腫瘤的發生。蟲草素是冬蟲夏草中主要的生物活性成分，據先前的研究顯示，通過調節 MAPK 相關途徑、引起細胞週期停滯、細胞凋亡和細胞自噬等方式可以抑制腫瘤發生，如肝癌、結腸癌、乳癌和肺癌等。先前實驗室已經表明，蟲草素可以分別在小鼠萊氏腫瘤細胞 (MA-10) 和小鼠萊氏前驅細胞 (TM3) 中抑制體外和體內的細胞增殖和腫瘤形成。因此，我們假設蟲草素可以在 FGF9 刺激的 MA-10 和/或 TM3 細胞中誘導細胞凋亡和/或細胞自噬。在本研究中，使用 MA-10 和 TM3 細胞來確定蟲草素如何在 FGF9 的刺激下調節細胞死亡。數據表明，蟲草素可以抑制細胞活力和集落形成的能力，並在有 FGF9 處理的清況下促使 MA-10 和 TM3 細胞發生形態學變化。流式細胞儀的數據和西方墨點法的結果進一步表明，在 FGF9 處理過後 MA-10 細胞中，蟲草素可以透過裂解 caspase-8、-9、-3 和 PARP 來誘導細胞凋亡，但在 TM3細胞中則不然。另一方面，對 FGF9 處理 TM3 細胞進行流式細胞儀檢測 AO 染色、免疫熒光染色和 LC3-II 蛋白表達，發現 TM3 細胞均會受到蟲草素的影響。出乎意料的是，在 FGF9 處理的 TM3 細胞中，蟲草素並未誘導與自噬途徑相關的 Atg5-12 和 beclin-1 等蛋白的表達。在 MA-10 細胞中，LC3-II、beclin-1 和 p62 的表達在 FGF9 存在的情況下不會受蟲草素所誘導，表明蟲草素不會在MA-10 細胞中誘導細胞自噬的發生。此外，抑制 ERK 和細胞自噬會使蟲草素誘導 FGF9 刺激的 MA-10 細胞發生死亡的效果增加。說明了 ERK 信號在兩種細胞中都受到蟲草素和 FGF9 的調節。在同種異體移植的模型中，對嚴重聯合免疫缺陷（NON-SCID）小鼠皮下注射了 MA-10 細胞使腫瘤產生，實驗的結果表明， FGF9 的存在下，蟲草素可以顯著抑制腫瘤生長，並且在腫瘤組織中觀察到，蟲草素可以抑制 cleaved caspase-3 的表達，暗示了蟲草素透過誘導caspase cascade 來抑制腫瘤生長。此外，與單獨處理 FGF9 的組別相比，蟲草素和 U0126 的共同處理也顯著抑制了 FGF9 刺激的腫瘤生長，進一步證實 ERK信號在該事件中的參與。綜上所述，蟲草素可在 FGF9 存在的情況下分別誘導MA-10 細胞發生細胞凋亡和 TM3 細胞發生細胞自噬，其中這些事件涉及了caspase 和 ERK 的訊號途徑。

Fibroblast growth factor 9 (FGF9) is a member of FGF family. In testis, abnormal expression of FGF9 can promote tumorigenesis. Cordycepin is a major bioactive component in fungus Cordyceps sinensis, and it has been reported to inhibit various tumors, such as liver, colon, breast and lung, via cell cycle arrest, apoptosis and/or autophagy with the regulation of MAPK pathways. We have shown that cordycepin could suppress cell proliferation and tumor formation in vitro and in vivo in MA-10 mouse Leydig tumor cells and TM3 mouse Leydig progenitor cells, respectively. Accordingly, we hypothesized that cordycepin could induce apoptosis and/or autophagy in FGF9-treated MA-10 and/or TM3 cells. In the present study, thus, MA-10 and TM3 cells were used to determine how cordycepin regulated MA-10 and TM3 Leydig cell death under FGF9 treatment. Data show that cordycepin could inhibit cell viability and colony formation with morphological change related to cell death in FGF9-treated MA-10 and TM3 cells. Flow cytometry and western blotting results further showed that cordycepin could induce apoptosis through the expression of cleaved caspase-8, -9, -3 and PARP in FGF9-treated MA-10 cells, but not in TM3 cells. Interestingly, AO staining detection by flow cytometry, immunofluorescent staining and the protein expression of LC3-II were induced by cordycepin in FGF9-treated TM3 cells. Unexpectedly, the expression of Atg5-12 and beclin-1, related to LC3 autophagic pathway, were not induced by cordycepin in FGF9-treated TM3 cells. In MA-10 cells, the expression of LC3-II, beclin-1 and p62 were not induced by cordycepin with the presence of FGF9, suggesting cordycepin would not induce autophagy in MA-10 cells. Moreover, inhibition of ERK signal pathway and autophagy would enhance cordycepin-induced cell death effects in FGF9-treated MA- 10 cells, referring that ERK signaling was modulated with cordcyepin and FGF9 treatments in both cell types. In allograft in vivo study, results of subcutaneous injection of MA-10 cells to the severe combined immunodeficiency (NOD-SCID) mice showed that cordycepin could significantly suppress tumor growth with the presence of FGF9, and the expression of cleaved caspase-3 could be observed in tumor tissue, implying cordycepin induced caspase cascade to suppress tumor growth. Furthermore, cotreatment of cordycepin and U0126 also significantly suppressed tumor growth with the presence of FGF9 as compared to the FGF9 alone group, further confirming the involvement of ERK signaling in this event. In conclusion, cordycepin could induce MA-10 cell apoptosis and TM3 cell autophagy with the presence of FGF9, respectively, and caspase and ERK pathways were involved.

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