台灣蜂膠衍生物通過誘導內質網應激和激活轉錄因子-3誘導人肝癌細胞凋亡
A Taiwanese Propolis Derivative Induces Apoptosis through Inducing Endoplasmic Reticular Stress and Activating Transcription Factor-3 in Human Hepatoma Cells
版權所有©2013Fat-Moon Suketal.這是根據知識共享署名許可分發的開放獲取文章,其中規定了無限制使用,分發和重新製作,提供了原創性功能。
激活轉錄因子(ATF-)3,一種應激誘導型轉錄因子,在各種應激條件下迅速上調,在誘導癌細胞凋亡中起重要作用.NBM-TP-007-GS-002(GS-002)是一種台灣蜂膠素propolin G(PPG)衍生物。在本研究中,我們在體外研究了人肝癌Hep3B和HepG2細胞中GS-002的抗腫瘤作用。首先,我們發現GS-02顯著抑制細胞增殖並誘導細胞凋亡的劑量依賴性。在GS-002處理的細胞中發現幾種主要的凋亡指標,例如半胱天冬酶-3,半胱天冬酶-9和聚(ADP-核糖)聚合酶(PARP)的切割形式。 GS-002還誘導內質網(ER)激活,如通過ER激活反應蛋白包括葡萄糖調節蛋白78(GRP78),生長停滯和DNA損傷誘導基因153(GADD153),磷酸化脫氧核糖核酸因子2α(eIF2α) ),磷酸化蛋白質內質網 - 宿主激酶(PERK)和ATF-3。 ATF-3表達的誘導是由有絲分裂原激活的蛋白激酶(MAPK),信號轉導通路在COS-002處理的細胞中進行的。此外,我們發現GS-002在ATF-3表達細胞中誘導更多的癌細胞的凋亡。這些結果表明,蜂膠衍生物GS-002的凋亡誘導通過ER脅迫和ATF-3-依賴性通路部分介導,而GS-002具有作為抗腫瘤藥物發展的潛力。
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Activating transcription factor-(ATF-) 3, a stress-inducible transcription factor, is rapidly upregulated under various stress conditions and plays an important role in inducing cancer cell apoptosis.NBM-TP-007-GS-002(GS-002) is a Taiwanese propolin G (PPG) derivative. In this study, we examined the antitumor effects of GS-002 in human hepatoma Hep3B and HepG2 cells in vitro.First,we found that GS-02 significantly in hibited cell proliferation and induced cell apoptosis in dose-dependent manners. Several main apoptotic indicators were found in GS-002-treated cells, such as the cleaved forms of caspase-3, caspase-9, and poly(ADP-ribose) polymerase (PARP). GS-002 also induced endoplasmic reticular (ER) stress as evidenced by increases in ER stress-responsive proteins including glucose-regulated protein 78 (GRP78), growth arrest- and DNA damage-inducible gene 153 (GADD153),phosphorylate deukaryoticinitiation factor2𝛼(eIF2𝛼),phosphorylatedproteinendoplasmic-reticular-residentkinase (PERK), and ATF-3. The induction of ATF-3 expression was mediated by mitogen-activated protein kinase (MAPK) signaling pathwaysinGS-002-treatedcells.Further more,we found that GS-002 induced more cell apoptosis in ATF-3-over expressing cells. These results suggest that the induction of apoptosis by the propolis derivative,GS-002,is partially mediated through ER stress and ATF-3-dependentpathways,andGS-002 has the potential for development as an antitumor drug.