Increased furin activity enhances the malignant phenotype of human head and neck cancer cells
Increased furin activity enhances the malignant phenotype of human head and neck cancer cells
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DOI：
10.1016/s0002-9440(10)63838-2
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发表时间：
2003-02-01
影响因子：
6
通讯作者：
Klein-Szanto, A
中科院分区：
文献类型：
--
作者：
Bassi, DE;Mahloogi, H;Klein-Szanto, A
许多蛋白质是以不活跃的形式合成的，需要蛋白分解过程才能使它们变得活跃。各种蛋白水解酶；催化这些裂解反应。原蛋白转换酶是一类丝氨酸蛋白酶家族，能够激活底物，从而干预细胞外基质(ECM)的降解、细胞生长、分化和病毒致病。Furin是该家族的原型，参与了许多生理和病理过程。它的一些底物，如转化生长因子-β、MT-基质金属蛋白酶和IGFR-1已经被发现，在几个人类肿瘤中观察到了呋喃西林的过度表达。在这份报告中，我们证明了在体外和体内过表达Furin会导致低和中等侵袭潜能的人类肿瘤细胞的侵袭潜能显着增加。将呋喃脱氢酶基因导入SCC12和SCC15中，得到了高效的呋喃脱氢酶底物。体内侵袭实验显示侵袭能力增强。用合成的抑制剂十酰基-精氨酸-Val-Lys-Arg氯甲基酮(CMK)抑制呋喃西林的活性，在加工和体外侵袭方面都显示出显著的降低。在细胞中加入Furin后，细胞的增殖率有一定程度的提高。CMK处理使这一效应明显减弱。皮下肿瘤(S.C.)接种过表达呋喃西林的细胞比对照细胞更大且发育更早。Furin过表达导致侵袭和增殖相关底物的激活失衡，从而导致晚期恶性表型的获得。此外，抑制呋喃西林的活性会降低底物的活性、增殖率和癌细胞的侵袭潜能，这表明呋喃西林是一个潜在的治疗靶点。
Many proteins are synthesized as inactive proforms requiring a proteolytic processing to render them active. A variety of proteases; catalyze these cleavage reactions. Proprotein convertases are a family of serine proteases capable of activating substrates that will subsequently intervene in extracellular matrix (ECM) degradation, cell growth, differentiation and viral pathogenesis. Furin, the prototype of this family, has been implicated in many physiological and pathological processes. Some of its substrates such as TGF-beta, MT-MMP's, and IGFR-1 have been identified Overexpression of furin has been observed in several human tumors. in this report we demonstrate that overexpression of furin causes a significant increase in the invasive potential of human tumor cells of low and moderate aggressive potential in vitro and in vivo. SCC12 and SCC15 were transfected with furin cDNA, resulting in efficient processing of furin substrates. An in vivo invasion assay showed enhancement of invasive ability. Inhibition of furin activity with the synthetic inhibitor decanoyl-Arg-Val-Lys-Argchloromethyl-ketone, CMK, showed a significant decrease in both processing and in vitro invasiveness. A moderate enhancement in proliferation rate was observed when cells were transfected with furin. CMK treatment resulted in a marked reduction of this effect. Tumors obtained after subcutaneous (s.c.) inoculation of furin-overexpressing cells were larger and developed earlier than the controls. Furin overexpression caused an imbalance in the activation of invasion and proliferation-related substrates leading to the acquisition of an advanced malignant phenotype. In addition, inhibition of furin activity decreases substrate activation, proliferation rate, and invasive potential of cancer cells, suggesting that furin is a potentially useful target for therapeutics.