Determination of cell uptake pathways for tumor inhibitor lysyl oxidase propeptide.
Determination of cell uptake pathways for tumor inhibitor lysyl oxidase propeptide.
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DOI：
10.1016/j.molonc.2015.07.005
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发表时间：
2016-01
影响因子：
6.6
通讯作者：
Trackman PC
中科院分区：
文献类型：
--
作者：
Ozdener GB;Bais MV;Trackman PC
赖氨酰氧化酶前肽（LOX-PP）是由赖氨酰氧化酶前体（Pro-LOX）通过细胞外生物合成蛋白水解而衍生的。LOX-PP抑制乳腺癌和前列腺癌异种移植肿瘤生长，并具有肿瘤抑制活性。虽然已经确定了LOX-PP的几个细胞内靶点和分子作用机制，但尚未报道LOX-PP摄取途径。在这里，我们证明重组LOX-PP（rLOX-PP）的主要摄取途径是在PWR-1 E，PC 3，SCC 9，MDA-MB-231细胞系中的PI 3 K依赖性巨胞饮。次级途径似乎是动力蛋白和小窝依赖。高碱性rLOX-PP的离子性质在高pH和低pH下都提供缓冲能力。我们认为，rLOX-PP的缓冲能力，这有助于限制内体酸化，维持PI 3 K依赖性的巨胞饮内体，这反过来又可能促进LOX-PP内体逃逸到细胞质和观察到的相互作用与细胞质靶和核摄取。
The lysyl oxidase propeptide (LOX-PP) is derived from pro-lysyl oxidase (Pro-LOX) by extracellular biosynthetic proteolysis. LOX-PP inhibits breast and prostate cancer xenograft tumor growth and has tumor suppressor activity. Although, several intracellular targets and molecular mechanisms of action of LOX-PP have been identified, LOX-PP uptake pathways have not been reported. Here we demonstrate that the major uptake pathway for recombinant LOX-PP (rLOX-PP) is PI3K-dependent macropinocytosis in PWR-1E, PC3, SCC9, MDA-MB-231 cell lines. A secondary pathway appears to be dynamin- and caveola dependent. The ionic properties of highly basic rLOX-PP provide buffering capacity at both high and low pHs. We suggest that the buffering capacity of rLOX-PP, which serves to limit endosomal acidification, sustains PI3K-dependent macropinocytosis in endosomes which in turn is likely to facilitate LOX-PP endosomal escape into the cytoplasm and its observed interactions with cytoplasmic targets and nuclear uptake.