探討原薯蕷皂苷誘導人類子宮頸癌細胞凋亡之機制

Study on Molecular Mechanism of Protodioscin Induces Apoptosis in Human Cervical Cancer Cells

曾佳儀(Jia-Yi Tseng)

指導教授 ： 謝逸憲

中山醫學大學/醫學院/生化微生物免疫研究所/碩士(2017年)

摘要

Protodioscin中文名稱為原薯蕷皂苷，主要來自穿龍薯蕷(Dioscorea nipponica)以及蒺藜(Tribulus terrestris)根莖部所萃取的天然物之一。過去研究protodioscin被發現的生物功能中包括抗血脂、抗腫瘤及誘導癌細胞凋亡，但是目前protodioscin對於人類子宮頸癌的癌細胞之抗癌特性及分子機制仍不清楚。因此本研究目的在於探討protodioscin對於人類子宮頸癌細胞抗癌機轉及相關分子機制。本研究利用protodioscin處理人類子宮頸癌細胞，以MTT、annexin-V雙染方式證實protodioscin會誘導子宮頸癌細胞凋亡，同時protodioscin也會誘導caspase-3、-8、-9和PARP(poly(ADP-ribose) polymerase)活化。Protodioscin也會誘導粒線體膜電位改變、Bax蛋白表現增加、Bcl-2蛋白表現降低，造成cytochrome c釋放。另外也發現在protodioscin的處理下可誘發內質網壓力(ER stress)，當細胞產生ER stress時，GRP78 (BiP)、PERK、p-eIF-2α、ATF-4 和CHOP磷酸化都有明顯增加的現象，但IRE-1α不受到影響。同時我們發現protodioscin也會誘導ROS (Reactive oxygen species)產生。綜合以上結果證實protodioscin會誘導ROS的產生、ER stress訊號途徑以及內、外在凋亡途徑，進而促使細胞凋亡現象。我們的研究說明，protodioscin在子宮頸癌會透過多方面訊息傳導路徑來誘導癌細胞凋亡，顯示protodioscin當作抗癌藥物的發展上深具潛力。

關鍵字

原薯蕷皂苷子宮頸癌 ； 細胞凋亡

並列摘要

Protodioscin (PD), one of the nature extracts from Dioscorea nipponica and the root and stem of Tribulus terrestris. Protodioscin has been found in biological functions including neuroprotection, anti-proliferation, and process anti-cancer potential. However, protodioscin is still unclear for the anticancer properties and molecular mechanisma of human cervical cancer. Therefore, this study was to investigate the anti-cancer and molecular mechanism of protodioscin on human cervical cancer. In the present study, we reported that protodioscin inhibited cell viability, induced the cell apoptosis and mitochondrial dysfunction of HeLa and C33A cells in dose-dependent manner. Protodioscin also significant increased the activation of caspase-3, -8, -9, -PARP and Bax, decreased Bcl-2 expression. In addition, we also observed that protodioscin induced ER stress and ER stress signaling pathway including the increased expression of Grp78 (BiP), PERK, phosphorylated of eIF-2α, ATF-4 and CHOP, but not IRE1α. In addition, protodioscin increased the levels of reactive oxygen species stress in human cervical cancer cells. Taken together, these findings shown that induction of ER stress via a PERK/p-eIF-2α/ATF4/CHOP, and ROS-dependent pathway may be an important mechanism by which protodioscin induces apoptosis in human cervical cancer cells. Based on the above, these results suggested that protodioscin potentially could be developed as an anti-cancer agent for treatment of human cervical cancer.

並列關鍵字

Protodioscin ； Cervical cancer ； apoptosis

參考文獻

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