细胞外压力通过一种需要蛋白激酶C（PKC）和酪氨酸激酶信号的机制刺激结肠癌细胞增殖。
Extracellular pressure stimulates colon cancer cell proliferation via a mechanism requiring PKC and tyrosine kinase signals.
作者信息
Walsh M F, Woo R K-Y, Gomez R, Basson M D
机构信息
Wayne State University School of Medicine, John D. Dingell VAMC, Detroit, MI 48201-1932, USA.
出版信息
Cell Prolif. 2004 Dec;37(6):427-41. doi: 10.1111/j.1365-2184.2004.00324.x.
UNLABELLED
Pressure in colonic tumours may increase during constipation, obstruction or peri-operatively. Pressure enhances colonocyte adhesion by a c-Src- and actin-cytoskeleton-dependent PKC-independent pathway. We hypothesized that pressure activates mitogenic signals.
METHODS
Malignant colonocytes on a collagen I matrix were subjected to 15 mmHg pressure. ERK, p38, c-Src and Akt phosphorylation and PKCalpha redistribution were assessed by western blot after 30 min and PKC activation by ELISA. Cells were counted after 24 h and after inhibition of each signal, tyrosine phosphorylation or actin depolymerization.
RESULTS
Pressure time-dependently increased SW620 and HCT-116 cell counts on collagen or fibronectin (P < 0.01). Pressure increased the SW620 S-phase fraction from 28 +/- 1 to 47 +/- 1% (P = 0.0002). Pressure activated p38, ERK, and c-Src (P < 0.05 each) but not Akt/PKB. Pressure decreased cytosolic PKC activity, and translocated PKCalpha to a membrane fraction. Blockade of p38, ERK, c-Src or PI-3-K or actin depolymerization did not inhibit pressure-stimulated proliferation. However, global tyrosine kinase blockade (genistein) and PKC blockade (calphostin C) negated pressure-induced proliferation.
CONCLUSIONS
Extracellular pressure stimulates cell proliferation and activates several signals. However, the mitogenic effect of pressure requires only tyrosine kinase and PKCalpha activation. Pressure may modulate colon cancer growth and implantation by two distinct pathways, one stimulating proliferation and the other promoting adhesion.
未标记
结肠肿瘤内压力在便秘、梗阻或围手术期可能会升高。压力通过一种不依赖蛋白激酶C（PKC）且依赖c-Src和肌动蛋白细胞骨架的途径增强结肠上皮细胞黏附。我们推测压力会激活促有丝分裂信号。
方法
将胶原I基质上的恶性结肠上皮细胞置于15 mmHg压力下。30分钟后通过蛋白质印迹法评估细胞外信号调节激酶（ERK）、p38、c-Src和蛋白激酶B（Akt）的磷酸化以及PKCα的重新分布，并通过酶联免疫吸附测定法评估PKC激活情况。在24小时后以及抑制每种信号、酪氨酸磷酸化或肌动蛋白解聚后进行细胞计数。
结果
压力使SW620和HCT-116细胞在胶原或纤连蛋白上的数量随时间增加（P < 0.01）。压力使SW620细胞的S期比例从28±1%增加到47±1%（P = 0.0002）。压力激活了p38、ERK和c-Src（各P < 0.05），但未激活Akt/PKB。压力降低了胞质PKC活性，并使PKCα转移至膜组分。阻断p38、ERK、c-Src或磷脂酰肌醇-3激酶（PI-3-K）或肌动蛋白解聚均未抑制压力刺激的增殖。然而，全局酪氨酸激酶阻断剂（染料木黄酮）和PKC阻断剂（钙泊三醇）消除了压力诱导的增殖。
结论
细胞外压力刺激细胞增殖并激活多种信号。然而，压力的促有丝分裂作用仅需要酪氨酸激酶和PKCα激活。压力可能通过两种不同途径调节结肠癌生长和植入，一种刺激增殖，另一种促进黏附。
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