V-ATPase inhibition increases cancer cell stiffness and blocks membrane related Ras signaling - a new option for HCC therapy.
V-ATPase inhibition increases cancer cell stiffness and blocks membrane related Ras signaling - a new option for HCC therapy.
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DOI：
10.18632/oncotarget.14339
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发表时间：
2017-02-07
期刊：
影响因子：
--
通讯作者：
von Schwarzenberg K
中科院分区：
文献类型：
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作者：
Bartel K;Winzi M;Ulrich M;Koeberle A;Menche D;Werz O;Müller R;Guck J;Vollmar AM;von Schwarzenberg K
肝细胞癌（HCC）是全球第五大常见癌症，也是癌症相关死亡的第三大原因。然而，治疗选择有限，迫切需要开发新的策略。目前，靶向癌细胞脂质和胆固醇代谢正在引起人们的兴趣，特别是关于HCC。高胆固醇水平支持增殖、膜相关的促有丝分裂信号传导并增加细胞柔软性，导致肿瘤进展、恶性和侵袭潜力。然而，针对癌症治疗的胆固醇代谢的有效方法仍然缺失。V-ATP酶抑制剂archazolid最近被证明干扰胆固醇代谢。在我们的研究中，我们报告了一种新的治疗潜力的V-ATP酶抑制剂在肝细胞癌中通过改变癌细胞的机械表型，导致减少增殖信号。Archazolid导致游离胆固醇的细胞消耗，导致癌细胞的细胞硬度和膜极性增加，而肝细胞不受影响。改变的膜组成降低了膜流动性，并导致抑制膜相关的Ras信号传导，导致体外和体内增殖降低。V-ATP酶抑制代表了恶性HCC细胞中细胞生物物理特性和增殖信号选择性之间的新联系，为针对HCC的有吸引力的创新策略提供了基础。
Hepatocellular carcinoma (HCC) is the fifth most frequent cancer worldwide and the third leading cause of cancer-related death. However, therapy options are limited leaving an urgent need to develop new strategies. Currently, targeting cancer cell lipid and cholesterol metabolism is gaining interest especially regarding HCC. High cholesterol levels support proliferation, membrane-related mitogenic signaling and increase cell softness, leading to tumor progression, malignancy and invasive potential. However, effective ways to target cholesterol metabolism for cancer therapy are still missing. The V-ATPase inhibitor archazolid was recently shown to interfere with cholesterol metabolism. In our study, we report a novel therapeutic potential of V-ATPase inhibition in HCC by altering the mechanical phenotype of cancer cells leading to reduced proliferative signaling. Archazolid causes cellular depletion of free cholesterol leading to an increase in cell stiffness and membrane polarity of cancer cells, while hepatocytes remain unaffected. The altered membrane composition decreases membrane fluidity and leads to an inhibition of membrane-related Ras signaling resulting decreased proliferation in vitro and in vivo. V-ATPase inhibition represents a novel link between cell biophysical properties and proliferative signaling selectively in malignant HCC cells, providing the basis for an attractive and innovative strategy against HCC.