Xu Qingyun, Karouji Yutaka, Kobayashi Michimoto, Ihara Sayoko, Konishi Hiroaki, Fukui Yasuhisa
Laboratory of Biological Chemistry, Department of Applied Biological Chemistry, Faculty of Agricultural and Life Science, Graduate School of Agricultural and Life Science, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
Oncogene. 2003 Aug 28;22(36):5537-44. doi: 10.1038/sj.onc.1206796.
Signet-ring cell carcinoma is classified in poorly differentiated adenocarcinoma with an aggressive nature and a poor prognosis. We have shown that the activation of PI 3-kinase in highly differentiated adenocarcinomas induces loss of cell-cell contact and formation of vacuoles, giving phenotypes similar to those of signet-ring cell lines. SB203580, a potent p38 MAP kinase inhibitor, blocked this transition, and expression of an active form of MKK6 (MKK6DA), an activator of p38 MAP kinase, gave effects similar to those induced by expression of the active form of PI 3-kinase (BD110), although formation of large vacuoles was not induced. Activation of MKK3, another activator of p38 MAP kinase, was activated in native signet-ring carcinoma cell lines. Anchorage-independent growth of signet-ring cell lines was inhibited by LY294002 or SB203580. These results suggest that p38 MAP kinase is functioning downstream of PI 3-kinase in signaling of the malignant phenotype. Secretion of mucins was enhanced in BD110-expressing cells, but not in MKK6DA-expressing cells, suggesting that secretion of mucins is independent of the MKK6-p38 MAP kinase cascade. Thus, there may be at least two pathways, p38 MAP kinase-dependent and -independent, which are involved in regulation of cell-cell contact and the protein secretion system, respectively.
印戒细胞癌归类于低分化腺癌，具有侵袭性且预后较差。我们已经表明，在高分化腺癌中PI 3激酶的激活会导致细胞间接触丧失和空泡形成，产生与印戒细胞系相似的表型。SB203580是一种有效的p38丝裂原活化蛋白激酶抑制剂，可阻断这种转变，而p38丝裂原活化蛋白激酶的激活剂MKK6的活性形式（MKK6DA）的表达产生的效果与PI 3激酶活性形式（BD110）表达所诱导的效果相似，尽管未诱导大空泡的形成。p38丝裂原活化蛋白激酶的另一种激活剂MKK3在天然印戒癌细胞系中被激活。印戒细胞系的非贴壁依赖性生长受到LY294002或SB203580的抑制。这些结果表明，在恶性表型信号传导中，p38丝裂原活化蛋白激酶在PI 3激酶的下游发挥作用。在表达BD110的细胞中粘蛋白分泌增强，但在表达MKK6DA的细胞中未增强，这表明粘蛋白的分泌独立于MKK6-p38丝裂原活化蛋白激酶级联反应。因此，可能至少有两条途径，分别是p38丝裂原活化蛋白激酶依赖性和非依赖性途径，它们分别参与细胞间接触和蛋白质分泌系统的调节。
