Oncogenic activation of Pak1-dependent pathway of macropinocytosis determines BCG entry into bladder cancer cells.
Oncogenic activation of Pak1-dependent pathway of macropinocytosis determines BCG entry into bladder cancer cells.
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DOI：
10.1158/0008-5472.can-12-1882
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发表时间：
2013-02-01
期刊：
影响因子：
11.2
通讯作者：
Glickman MS
中科院分区：
文献类型：
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作者：
Redelman-Sidi G;Iyer G;Solit DB;Glickman MS
卡介苗 (BCG) 是牛分枝杆菌的减毒菌株，广泛用作结核病疫苗，并可有效治疗浅表性膀胱癌。尽管是最成功的癌症生物疗法，但其作用机制和反应决定因素仍然不清楚。在这里，我们建立了一个模型系统来分析 BCG 与膀胱癌细胞的相互作用，用它来表明这些细胞对 BCG 感染的易感性存在显着差异。出乎意料的是，膀胱癌细胞对 BCG 的摄取是通过巨胞饮作用而不是吞噬作用发生的。 BCG 进入膀胱癌细胞依赖于 Rac1、Cdc42 及其效应激酶 Pak1。 BCG 允许型和 BCG 耐药性膀胱癌细胞之间的敏感性差异是由于激活巨胞饮作用的信号通路的致癌激活，其中 PI3K 激活独立于 Akt 刺激 BCG 摄取。同样，激活的 Ras 强烈激活 Pak1 依赖性的 BCG 摄取。这些结果表明，巨胞饮作用的致癌激活决定了膀胱癌细胞对 BCG 的摄取，这意味着肿瘤对 BCG 的反应可能受治疗的癌细胞中存在的特定突变的控制。
Bacille Calmette-Guerin (BCG) is an attenuated strain of Mycobacterium bovis that is used widely as a vaccine for tuberculosis and is used as an effective treatment for superficial bladder carcinoma. Despite being the most successful cancer biotherapy, its mechanism of action and response determinants remain obscure. Here we establish a model system to analyze BCG interaction with bladder cancer cells, using it to show that these cells vary dramatically in their susceptibility to BCG infection. Unexpectedly, the uptake of BCG by bladder cancer cells occurs by macropinocytosis rather than phagocytosis. BCG entry into bladder cancer cells relied upon Rac1, Cdc42 and their effector kinase Pak1. The difference in susceptibility between BCG-permissive and BCG-resistant bladder cancer cells was due to oncogenic activation of signaling pathways that activate macropinocytosis, with PI3K activation stimulating BCG uptake independently of Akt. Similarly, activated Ras strongly activated Pak1-dependent uptake of BCG. These results reveal that oncogenic activation of macropinocytosis determines BCG uptake by bladder cancer cells, implying that tumor responsiveness to BCG may be governed by the specific mutations present in the treated cancer cell.