Sawada Kenjiro, Morishige Ken ichirou, Tahara Masahiro, Ikebuchi Yoshihide, Kawagishi Rikako, Tasaka Keiichi, Murata Yuji
Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, Japan.
Gynecol Oncol. 2002 Dec;87(3):252-9. doi: 10.1006/gyno.2002.6831.
The level of lysophosphatidic acid (LPA) is elevated in patients with ovarian cancer, and LPA has been reported to have a pivotal role in cancer dissemination. In the current study, the effect of LPA on the motility of ovarian cancer cells was investigated.
We analyzed the effects of LPA on the migration activity, the focal adhesion formation, and the tyrosine phosphorylation of focal adhesion proteins in human ovarian cancer cell lines Caov-3 and OVCAR-3. Inhibitors of the small GTPase Rho, one of its downstream effectors (Rho-associated kinase (ROCK)), myosin light chain kinase (MLCK), and myosin light chain (MLC) phosphatase were used to examine the mechanism of LPA-induced cellular effects.
LPA enhanced the migration of ovarian cancer cells and facilitated their invasion. Rho and ROCK played essential roles in the migratory process, as evidenced by the inhibition of migration and focal adhesion formation of cancer cells by Clostridium botulinum C3 exoenzyme (C3), an inhibitor of Rho, or Y-27632, an inhibitor of ROCK. LPA also evoked the formation of focal adhesions and tyrosine phosphorylation of focal adhesion kinase and paxillin, all of which were inhibited by C3 or Y-27632.
These results suggest that LPA induced the migration of ovarian cancer cells, at least in part, through accelerated formation of focal adhesions mediated by Rho/ROCK-induced actomyosin contractility. This study may provide the basis for new therapies to control the metastasis of ovarian cancer.
卵巢癌患者溶血磷脂酸（LPA）水平升高，且有报道称LPA在癌症播散中起关键作用。在本研究中，我们探究了LPA对卵巢癌细胞运动性的影响。
我们分析了LPA对人卵巢癌细胞系Caov-3和OVCAR-3迁移活性、粘着斑形成以及粘着斑蛋白酪氨酸磷酸化的影响。使用小GTP酶Rho及其下游效应器之一（Rho相关激酶（ROCK））、肌球蛋白轻链激酶（MLCK）和肌球蛋白轻链（MLC）磷酸酶的抑制剂来研究LPA诱导细胞效应的机制。
LPA增强了卵巢癌细胞的迁移并促进其侵袭。Rho和ROCK在迁移过程中起重要作用，这一点可通过肉毒杆菌C3外毒素（C3，一种Rho抑制剂）或Y-27632（一种ROCK抑制剂）抑制癌细胞迁移和粘着斑形成得到证明。LPA还诱导了粘着斑的形成以及粘着斑激酶和桩蛋白的酪氨酸磷酸化，而这些均被C3或Y-27632抑制。
这些结果表明，LPA至少部分通过Rho/ROCK诱导的肌动球蛋白收缩性介导的粘着斑加速形成来诱导卵巢癌细胞迁移。本研究可能为控制卵巢癌转移的新疗法提供依据。
