Cathepsin L inhibition by the small molecule KGP94 suppresses tumor microenvironment enhanced metastasis associated cell functions of prostate and breast cancer cells.
Cathepsin L inhibition by the small molecule KGP94 suppresses tumor microenvironment enhanced metastasis associated cell functions of prostate and breast cancer cells.
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DOI：
10.1007/s10585-013-9590-9
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发表时间：
2013-10
影响因子：
4
通讯作者：
Siemann, Dietmar W.
中科院分区：
文献类型：
--
作者：
Sudhan, Dhivya R.;Siemann, Dietmar W.
转移仍然是乳腺癌和前列腺癌患者治疗失败、预后差和死亡率高的主要原因。包括缺氧和酸性pH值在内的异常微环境是大多数实体瘤的常见特征，长期以来与转移增强和患者预后不良有关。显然，需要新的方法来降低转移发生率并提高癌症患者的总体生存率。组织蛋白酶L（CTSL）在肿瘤细胞播散中的关键作用导致了新的组织蛋白酶L抑制策略的发展。本研究评估了KGP 94（CTSL的小分子抑制剂）在正常和异常微环境条件下损害前列腺癌（PC-3 ML）和乳腺癌（MDAMB- 231）细胞的转移表型的能力。为了评估CTSL在缺氧和酸中毒触发的转移相关细胞功能中的作用，在与肿瘤微环境相关的条件下测定分泌的CTSL水平。急性暴露于缺氧或酸性条件下，通过增加细胞内CTSL水平或通过激活溶酶体胞吐作用或两者，显著升高分泌的CTSL水平，这取决于肿瘤类型。CTSL分泌的增加密切地促进了肿瘤细胞的迁移和侵袭，提示CTSL可能是肿瘤微环境触发转移的重要因素。重要的是，KGP 94治疗导致在正常和异常微环境条件下肿瘤细胞侵袭和迁移的显著减弱，这表明它可能具有作为抗转移剂的显著效用。
Metastasis remains the major cause of therapeutic failure, poor prognosis and high mortality in breast and prostate cancer patients. Aberrant microenvironments including hypoxia and acidic pH are common features of most solid tumors that have been long associated with enhanced metastasis and poor patient outcomes. Novel approaches to reduce metastatic incidences and improve overall survival of cancer patients clearly are needed. The crucial role of Cathepsin L (CTSL) in the dissemination of tumor cells has led to the development of novel cathepsin L inhibition strategies. The present study evaluated the ability of KGP94, a small molecule inhibitor of CTSL, to impair the metastatic phenotype of prostate (PC-3ML) and breast (MDAMB- 231) cancer cells both under normal and aberrant microenvironmental conditions. To assess the role of CTSL in hypoxia and acidosis triggered metastasis associated cell functions, secreted CTSL levels were determined under conditions pertinent to the tumor microenvironment. Acute exposures to hypoxic or acidic conditions significantly elevated secreted CTSL levels either through an increase in intracellular CTSL levels or through activation of lysosomal exocytosis or both, depending on the tumor type. Increases in CTSL secretion closely paralleled enhanced tumor cell migration and invasion suggesting that CTSL could be an essential factor in tumor microenvironment triggered metastasis. Importantly, KGP94 treatment led to marked attenuation of tumor cell invasion and migration under both normal and aberrant microenvironmental conditions suggesting that it may have significant utility as an anti-metastatic agent.
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影响因子：
5.8
作者：
Ervin H;Cox JL
通讯作者：
Cox JL
DOI：
10.1038/sj.neo.7900037
发表时间：
1999-08-01
期刊：
Neoplasia (New York)
影响因子：
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作者：
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通讯作者：
Trawick, Mary Lynn
DOI：
10.1016/j.bbagen.2010.03.003
发表时间：
2010-06-01
影响因子：
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作者：
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通讯作者：
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影响因子：
8.4
作者：
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通讯作者：
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