Mason Charlene K, McFarlane Suzanne, Johnston Patrick G, Crowe Paul, Erwin Pauline J, Domostoj Mathias M, Campbell F Charles, Manaviazar Soraya, Hale Karl J, El-Tanani Mohamed
Centre for Cancer Research and Cell Biology, Queen's University Belfast, Northern Ireland, UK.
Mol Cancer Ther. 2008 Mar;7(3):548-58. doi: 10.1158/1535-7163.MCT-07-2251.
Effective inhibitors of osteopontin (OPN)-mediated neoplastic transformation and metastasis are still lacking. (-)-Agelastatin A is a naturally occurring oroidin alkaloid with powerful antitumor effects that, in many cases, are superior to cisplatin in vitro. In this regard, past comparative assaying of the two agents against a range of human tumor cell lines has revealed that typically (-)-agelastatin A is 1.5 to 16 times more potent than cisplatin at inhibiting cell growth, its effects being most pronounced against human bladder, skin, colon, and breast carcinomas. In this study, we have investigated the effects of (-)-agelastatin A on OPN-mediated malignant transformation using mammary epithelial cell lines. Treatment with (-)-agelastatin A inhibited OPN protein expression and enhanced expression of the cellular OPN inhibitor, Tcf-4. (-)-Agelastatin A treatment also reduced beta-catenin protein expression and reduced anchorage-independent growth, adhesion, and invasion in R37 OPN pBK-CMV and C9 cell lines. Similar effects were observed in MDA-MB-231 and MDA-MB-435s human breast cancer cell lines exposed to (-)-agelastatin A. Suppression of Tcf-4 by RNA interference (short interfering RNA) induced malignant/invasive transformation in parental benign Rama 37 cells; significantly, these events were reversed by treatment with (-)-agelastatin A. Our study reveals, for the very first time, that (-)-agelastatin A down-regulates beta-catenin expression while simultaneously up-regulating Tcf-4 and that these combined effects cause repression of OPN and inhibition of OPN-mediated malignant cell invasion, adhesion, and colony formation in vitro. We have also shown that (-)-agelastatin A inhibits cancer cell proliferation by causing cells to accumulate in the G(2) phase of cell cycle.
目前仍缺乏有效的骨桥蛋白（OPN）介导的肿瘤转化和转移抑制剂。（-）-海兔毒素A是一种天然存在的海兔素生物碱，具有强大的抗肿瘤作用，在许多情况下，其体外抗肿瘤效果优于顺铂。在这方面，过去对这两种药物针对一系列人类肿瘤细胞系进行的比较检测表明，通常（-）-海兔毒素A在抑制细胞生长方面比顺铂强1.5至16倍，其对人类膀胱癌、皮肤癌、结肠癌和乳腺癌的作用最为显著。在本研究中，我们使用乳腺上皮细胞系研究了（-）-海兔毒素A对OPN介导的恶性转化的影响。用（-）-海兔毒素A处理可抑制OPN蛋白表达，并增强细胞OPN抑制剂Tcf-4的表达。（-）-海兔毒素A处理还降低了β-连环蛋白的蛋白表达，并减少了R37 OPN pBK-CMV和C9细胞系中不依赖贴壁的生长、黏附及侵袭。在暴露于（-）-海兔毒素A的MDA-MB-231和MDA-MB-435s人乳腺癌细胞系中也观察到了类似的效果。通过RNA干扰（小干扰RNA）抑制Tcf-4可诱导亲代良性Rama 37细胞发生恶性/侵袭性转化；值得注意的是，用（-）-海兔毒素A处理可逆转这些事件。我们的研究首次揭示，（-）-海兔毒素A下调β-连环蛋白表达，同时上调Tcf-4，这些联合作用导致OPN受到抑制，并在体外抑制OPN介导的恶性细胞侵袭、黏附和集落形成。我们还表明，（-）-海兔毒素A通过使细胞在细胞周期的G2期积累来抑制癌细胞增殖。
