Preferential cytotoxicity of the type I ribosome inactivating protein alpha-momorcharin on human nasopharyngeal carcinoma cells under normoxia and hypoxia.
Preferential cytotoxicity of the type I ribosome inactivating protein alpha-momorcharin on human nasopharyngeal carcinoma cells under normoxia and hypoxia.
复制标题
DOI：
10.1016/j.bcp.2014.03.004
复制
发表时间：
2014-06-01
影响因子：
5.8
通讯作者：
Cheung RC
中科院分区：
文献类型：
--
作者：
Pan WL;Wong JH;Fang EF;Chan YS;Ng TB;Cheung RC
所有原发性鼻咽癌（NPC）肿瘤都含有缺氧区域，这与局部控制下降和远处转移增加以及晚期NPC患者对化疗的抵抗有关。针对肿瘤组织中缺氧因子的靶向药物治疗是鼻咽癌治疗的重要途径之一。本研究从苦瓜种子中分离得到的I型核糖体失活蛋白α-苦瓜素（α-MMC），在常氧和氯化钴诱导的缺氧条件下，可降低人鼻咽癌CNE 2和HONE 1细胞的存活率，抑制其克隆形成。在常氧条件下，α-MMC对人鼻咽上皮细胞NP 69的细胞毒性较低。有趣的是，α-MMC抑制缺氧NPC中缺氧诱导因子1-α（HIF 1 α）和血管内皮生长因子（VEGF）的表达水平，以及人脐静脉内皮细胞的生长。进一步研究发现α-MMC作用于鼻咽癌细胞的内质网，下调未折叠蛋白反应（unfolded protein response，UPR）。α-MMC诱导鼻咽癌细胞凋亡的作用呈剂量和时间依赖性。它启动线粒体和死亡受体介导的CNE 2细胞凋亡信号，但对HONE 1细胞几乎没有任何影响。α-MMC使CNE 2细胞阻滞于G 0/G1期，HONE 1细胞阻滞于S期。总体而言，α-MMC对常氧和缺氧鼻咽癌细胞的抑制作用主要是通过阻断HIF 1 α、VEGF和UPR等生存信号通路，并触发线粒体或死亡受体介导的凋亡途径。提示α-MMC在鼻咽癌的预防和治疗中具有潜在的应用价值。
All primary nasopharyngeal carcinoma (NPC) tumors contain hypoxic regions which are implicated in decreased local control and increased distant metastases, as well as resistance to chemotherapy in advanced NPC patients. One of the promising therapeutic approaches for NPC is to use drugs that can target hypoxic factors in tumors. In the present investigation, the type I ribosome inactivating protein α-momorcharin (α-MMC), isolated from seeds of the bitter gourd Momordica charantia, reduced cell viability and inhibited clonogenic formation of human NPC CNE2 and HONE1 cells under normoxia and cobalt chloride-induced hypoxia. By comparison, α-MMC exhibited only slight cytotoxicity on human nasopharyngeal epithelial NP69 cells under normoxia. Interestingly, α-MMC suppressed the expression levels of hypoxia-inducible factor 1-alpha (HIF1α) and vascular endothelial growth factor (VEGF) in hypoxic NPC, as well as the growth of human umbilical vein endothelial cells. Further study disclosed that α-MMC targeted endoplasmic reticulum and down-regulated unfolded protein response (UPR) in NPC cells. Moreover, α-MMC induced apoptosis in NPC cells in a dose- and time-dependent manner. It initiated mitochondrial- and death receptor-mediated apoptotic signaling in CNE2 cells, but there was hardly any effect on HONE1 cells. In addition, α-MMC brought about G0/G1 phase cell cycle arrest in CNE2 cells and S phase arrest in HONE1 cells. Collectively, α-MMC preferentially exhibited inhibitory effect on normoxic and hypoxic NPC cells partly by blocking survival signaling (e.g. HIF1α, VEGF and UPR), and triggering apoptotic pathways mediated by mitochondria or death receptor. These observations indicate the potential utility of α-MMC for prophylaxis and therapy of NPC.
登录
查看更多内容
影响因子：
11.2
作者：
Fels DR;Ye J;Segan AT;Kridel SJ;Spiotto M;Olson M;Koong AC;Koumenis C
通讯作者：
Koumenis C
DOI：
10.1016/0020-711x(92)90371-7
发表时间：
1992-07-01
期刊：
INTERNATIONAL JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
CHAN, WY;NG, TB;YEUNG, HW
通讯作者：
YEUNG, HW
影响因子：
3.6
作者：
Gray, MD;Mann, M;Hendershot, LM
通讯作者：
Hendershot, LM
影响因子：
64.8
作者：
Calfon, M;Zeng, HQ;Ron, D
通讯作者：
Ron, D
影响因子：
5.3
作者：
Blais, JD;Filipenko, V;Bell, JC
通讯作者：
Bell, JC