Implications of Proprotein Convertases in Ovarian Cancer Cell Proliferation and Tumor Progression: Insights for PACE4 as a Therapeutic Target.
Implications of Proprotein Convertases in Ovarian Cancer Cell Proliferation and Tumor Progression: Insights for PACE4 as a Therapeutic Target.
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前蛋白转化酶在卵巢癌细胞增殖和肿瘤进展中的影响：PACE4作为治疗靶点的见解。
DOI：
10.1016/j.tranon.2014.04.008
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发表时间：
2014-05-09
影响因子：
5
通讯作者：
Day, Robert
中科院分区：
文献类型：
--
作者：
Longuespee, Remi;Couture, Frederic;Levesque, Christine;Kwiatkowska, Anna;Desjardins, Roxane;Gagnon, Sandra;Vergara, Daniele;Maffia, Michelle;Fournier, Isabelle;Salzet, Michel;Day, Robert
前蛋白转化酶是一类kexin样丝氨酸蛋白酶家族，其在单个和多个碱性残基处加工蛋白质。在预测和鉴定的PC底物中，越来越多的在癌症进展中具有功能的蛋白质表明PC可能是抗肿瘤药物的潜在靶点。为了支持这一观点，我们将PACE 4鉴定为参与前列腺癌增殖和进展的重要PC，与其他共表达的PC形成对比。本研究的目的是测试PC在卵巢癌细胞增殖和肿瘤进展中的重要性。基于组织表达谱，furin、PACE 4、PC 5/6和PC 7在原发肿瘤、腹水细胞和转移瘤中均显示出表达增加。这些PC也以可变水平在三种测试的模型卵巢细胞系（即SKOV 3、CAOV 3和OVCAR 3细胞）中表达。由于SKOV 3细胞密切代表卵巢癌细胞的PC表达谱，我们选择它们来测试PC沉默的效果，使用稳定的基因沉默shRNA策略来产生针对每个表达的PC的敲低SKOV 3细胞。体外和体内试验证实了PACE 4在维持SKOV 3细胞增殖中的作用，这在其他三种PC中没有观察到。我们还在所有三种细胞系上测试了PACE 4肽抑制剂，并观察到随后的细胞增殖减少，这与PACE 4表达相关。总的来说，这些数据支持PACE 4在促进卵巢癌细胞增殖中的作用，并为PACE 4作为潜在的治疗靶点提供了进一步的证据。
Proprotein convertases are a family of kexin-like serine proteases that process proteins at single and multiple basic residues. Among the predicted and identified PC substrates, an increasing number of proteins having functions in cancer progression indicate that PCs may be potential targets for antineoplastic drugs. In support of this notion, we identified PACE4 as a vital PC involved in prostate cancer proliferation and progression, contrasting with the other co-expressed PCs. The aim of the present study was to test the importance of PCs in ovarian cancer cell proliferation and tumor progression. Based on tissue-expression profiles, furin, PACE4, PC5/6 and PC7 all displayed increased expression in primary tumor, ascites cells and metastases. These PCs were also expressed in variable levels in three model ovarian cell lines tested, namely SKOV3, CAOV3 and OVCAR3 cells. Since SKOV3 cells closely represented the PC expression profile of ovarian cancer cells, we chose them to test the effects of PC silencing using stable gene-silencing shRNA strategy to generate knockdown SKOV3 cells for each expressed PC. In vitro and in vivo assays confirmed the role of PACE4 in the sustainment of SKOV3 cell proliferation, which was not observed with the other three PCs. We also tested PACE4 peptide inhibitors on all three cell lines and observed consequent reduced cell proliferation which was correlated with PACE4 expression. Overall, these data support a role of PACE4 in promoting cell proliferation in ovarian cancer and provides further evidence for PACE4 as a potential therapeutic target.
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DOI：
10.1097/pas.0b013e3181cf3d79
发表时间：
2010-03
期刊：
The American journal of surgical pathology
影响因子：
--
作者：
Kurman RJ;Shih IeM
通讯作者：
Shih IeM
影响因子：
11.2
作者：
Bassi, DE;De Cicco, RL;Klein-Szanto, AJP
通讯作者：
Klein-Szanto, AJP
影响因子：
2
作者：
Longuespee, Remi;Gagnon, Hugo;Salzet, Michel
通讯作者：
Salzet, Michel
影响因子：
3.7
作者：
Lewis-Tuffin LJ;Rodriguez F;Giannini C;Scheithauer B;Necela BM;Sarkaria JN;Anastasiadis PZ
通讯作者：
Anastasiadis PZ
影响因子：
8.4
作者：
Ferlay, J.;Steliarova-Foucher, E.;Bray, F.
通讯作者：
Bray, F.