研究肺癌細胞內信息傳導之調控 1. 磷酸化Akt於Mitomycin C引起之不良反應所扮演的角色 2. Semaphorin 6A於細胞凋亡之自我調控

To study the regulations of cell signaling in lung cancer cells: 1. The role of phosphorylated Akt in mitomycin C induced adverse responses. 2. Self-regulation of semaphorin 6A in apoptosis.

沈政瑩(Cheng-Ying Shen)

指導教授 ： 蔡孟勳

國立臺灣大學/生物資源暨農學院/生物科技研究所/博士(2017年)

https://doi.org/10.6342/NTU201700179

摘要

肺癌是世界上持續高踞癌症死亡主因的前幾位。肺癌同時也造成了癌症患友的家庭與社會的沉重負擔。在癌症細胞的發生過程中，癌症細胞內的訊息傳導，如有利於存活的磷酸化Akt與關掉能誘發細胞凋亡的路徑是需要的。許多化療藥物也是針對這些相關的訊息傳導路徑來設計。但是，有些抗癌藥物還是會引發一些藥物的不良反應，例如抗藥性的產生與癌症轉移。在本論文中，我們將利用兩篇研究來探討肺癌細胞面對化療藥物時的可能細胞訊息反應，與最新發現的semaphorin 6A對細胞凋亡的控制機制。
我們發現與同源母細胞株CL1-0相比，較惡性肺癌子細胞株CL1-5對mitomycin C (MMC)的抵抗能力較強。並且發現MMC會透過磷酸化Akt (p-Akt)的活化來增強CL1-5的細胞移動。在共同處理p-Akt 抑制劑與MMC之後則可以減低MMC產生的不良效應，並增加MMC的細胞毒性。因此磷酸化的Akt (p-Akt) 是造成MMC抗藥性與增強細胞移動的主因。
除此之外，本論文也將描述semaphorin 6A經由其細胞質內的蛋白質區與FADD結合所引發的細胞凋亡現象。此FADD與semaphorin 6A胞質內蛋白質區之結合現象更可藉由semaphorin 6A自身之胞質外蛋白質區(extracellular domain)來控制，進而降低胞質蛋白區所誘發之細胞凋亡的現象。
藉由本研究發現合併使用磷酸化Akt抑制劑與抗癌藥物能增進對惡性肺癌細胞的療效，與全新關於semaphorin 6A對細胞凋亡的調控，可以在未來於肺癌的臨床治療上有更好的貢獻。

關鍵字

磷酸化Akt ； MMC化療藥物 ； 肺癌細胞 ； semaphorin 6A膜蛋白 ； 細胞凋亡 ； semaphorin 6A胞質外蛋白質區

並列摘要

Lung cancer is the major cause of cancer-related death worldwide and brings significant socioeconomic effects to patients and their families. Cell signaling such as p-Akt activation for survival and silencing of cell death related pathways for evading senescence and apoptosis are required during lung carcinogenesis. Many drugs were developed against these signaling proteins for cancer therapy. Unfortunately, some anticancer-agents might induce adverse effects such as drug resistance or metastasis. In this thesis, two studies were used to elucidate the potential signaling within lung cancer cells in response to chemotherapeutic agents induced adverse effects, and the discovered activation of apoptosis in semaphorin 6A dependent regulation.
We found that the malignant lung cancer cells, CL1-5, were more resistant to mitomycin C than were the parental CL1-0 cells. Furthermore, cell migration was enhanced by MMC in CL1-5 cells. Administering a p-Akt inhibitor reduced the mitomycin C resistance, demonstrating that p-Akt is important in the mitomycin C resistance of CL1-5 cells. Our data suggest that in CL1-5 cells, the activity of p-Akt, may underlie the resistance to mitomycin C and enhance the cells’ migration abilities after drug treatment.
Moreover, we described the discovered functions of semaphorin 6A in regulating apoptosis via its cytosolic region through interaction with FADD, and the SEMA domain might act as a safety pin by attenuating the interaction between FADD to prevent cytosolic domain of semaphorin 6A induced apoptosis.
Overall, this thesis provides insights on an improved efficacy of chemotherapy by combining mitomycin C with a p-Akt inhibitor, and a newly discovered semaphorin 6A-regulated apoptosis signaling. We expect that the findings of this thesis can make contributions to lung cancer therapy.

並列關鍵字

p-Akt ； MMC ； lung cancer cells ； semaphorin 6A ； apoptosis ； SEMA domain of semaphorin 6A

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