Alendronate inhibits lysophosphatidic acid-induced migration of human ovarian cancer cells by attenuating the activation of rho.
Alendronate inhibits lysophosphatidic acid-induced migration of human ovarian cancer cells by attenuating the activation of rho.
复制标题
DOI：
--
复制
发表时间：
2002-11
期刊：
影响因子：
11.2
通讯作者：
Kenjiro Sawada;Ken‐ichirou Morishige;M. Tahara;Rikako Kawagishi;Y. Ikebuchi;K. Tasaka;Y. Murata
中科院分区：
文献类型：
--
作者：
Kenjiro Sawada;Ken‐ichirou Morishige;M. Tahara;Rikako Kawagishi;Y. Ikebuchi;K. Tasaka;Y. Murata
阿仑膦酸钠是一种含氮双膦酸盐，是一种有效的骨吸收抑制剂，用于治疗和预防骨质疏松症。最近的研究结果表明，阿仑膦酸盐和其他含氮双膦酸盐抑制甲羟戊酸途径，从而抑制该代谢产物的合成。这反过来又阻止了许多调节细胞生长、运动和侵袭的小GTP酶的异戊烯化。我们研究了阿仑膦酸钠对人卵巢癌细胞体外迁移的影响。溶血磷脂酸（LPA）通过促进Rho/Rho相关激酶信号传导诱导癌细胞迁移的剂量依赖性增加。阿仑膦酸钠以剂量依赖性方式抑制LPA诱导的癌细胞迁移。阿仑膦酸钠处理卵巢癌细胞导致Rho失活、细胞形态改变、应力纤维形成和粘着斑组装的丧失、肌球蛋白轻链磷酸化和粘着斑蛋白酪氨酸磷酸化的抑制，这些是细胞迁移的必要过程。阿仑膦酸钠对癌细胞的作用可以通过添加香叶基香叶醇来阻止，香叶基香叶醇是甲羟戊酸途径的代谢中间体。这些结果表明，阿仑膦酸钠抑制Rho激活通过阻止香叶基香叶基化，这导致抑制LPA诱导的人卵巢癌细胞的迁移。
Alendronate, a nitrogen-containing bisphosphonate, is a potent inhibitor of bone resorption used for the treatment and prevention of osteoporosis. Recent findings suggest that alendronate and other nitrogen-containing bisphosphonates inhibit the mevalonate pathway and thereby inhibit the synthesis of products derived from this metabolite. This, in turn, prevents the prenylation of a number of small GTPases, which regulate cell growth, motility, and invasion. We studied the effect of alendronate on in vitro migration of human ovarian cancer cells. Lysophosphatidic acid (LPA) induced a dose-dependent increase of migration of cancer cells by promoting Rho/Rho-associated kinase signaling. The induction of cancer cell migration by LPA was inhibited by the addition of alendronate in a dose-dependent manner. Treatment of ovarian cancer cells with alendronate resulted in inactivation of Rho, changes of cell morphology, loss of stress fiber formation, and focal adhesion assembly, and the suppression of phosphorylation of myosin light chain and tyrosine phosphorylation of focal adhesion proteins, which are essential processes for cell migration. The effects of alendronate on cancer cells were prevented by the addition of geranylgeranyol, which is the metabolic intermediate of the mevalonate pathway. These results suggest that alendronate inhibits Rho activation by preventing geranylgeranylation, which results in inhibition of LPA-induced migration of human ovarian cancer cells.