Chu Simon, Alexiadis Maria, Fuller Peter J
Prince Henry's Institute of Medical Research, Victoria, Australia.
Reprod Sci. 2009 Apr;16(4):397-407. doi: 10.1177/1933719108327589. Epub 2008 Dec 15.
Granulosa cell tumors of the ovary represent approximately 5% of malignant ovarian tumors. The molecular pathogenesis of granulosa cell tumors is not known but 2 human granulosa cell tumor-derived cell lines, COV434 and KGN, exhibit constitutive activation of the nuclear factor kappa-B (NFkappaB)-signaling pathway. The proteasomal inhibitor, bortezomib, has a complex mode of action which includes inhibition of NFkappaB signaling. We examined the effect of bortezomib on the COV434 and KGN cells. The COV434 and KGN cells both showed a dose-dependent inhibition of cell proliferation and viability in response to bortezomib together with an increase in apoptosis. This was achieved at concentrations within the range seen for clinically responsive tumors. The NFkappaB constitutive activity was not however decreased. Genes were identified that were regulated in both lines in response to bortezomib. This study suggests that advanced granulosa cell tumors, as represented by the cell lines, may respond to bortezomib either alone or in combination with other agents.
卵巢颗粒细胞瘤约占卵巢恶性肿瘤的5%。颗粒细胞瘤的分子发病机制尚不清楚，但两种源自人颗粒细胞瘤的细胞系COV434和KGN表现出核因子κB（NFκB）信号通路的组成性激活。蛋白酶体抑制剂硼替佐米具有复杂的作用模式，包括抑制NFκB信号传导。我们研究了硼替佐米对COV434和KGN细胞的影响。COV434和KGN细胞均显示出对硼替佐米的剂量依赖性细胞增殖抑制和活力降低，同时凋亡增加。这是在临床反应性肿瘤所见的浓度范围内实现的。然而，NFκB的组成性活性并未降低。鉴定出了两种细胞系中对硼替佐米有反应而被调节的基因。这项研究表明，以这些细胞系为代表的晚期颗粒细胞瘤可能单独或与其他药物联合对硼替佐米有反应。
