Kawada Manabu, Kawatsu Masaji, Masuda Tohru, Ohba Shun-ichi, Amemiya Masahide, Kohama Takafumi, Ishizuka Masaaki, Takeuchi Tomio
Institute for Chemotherapy, Microbial Chemistry Research Foundation, 18-24 Miyamoto, Numazu, Shizuoka 410-0301, Japan.
Int Immunopharmacol. 2003 Feb;3(2):179-88. doi: 10.1016/s1567-5769(02)00231-x.
Selective augmentation of natural killer (NK) cells can suppress tumor metastasis, but molecular targets for NK cell activation have not been identified. We report here that cytostatin (CTS), a novel specific inhibitor of protein phosphatase (PP) 2A, can inhibit B16 melanoma pulmonary metastasis by the expansion and activation of NK cells. CTS administration in vivo increased mRNA expression of Flt-3 ligand, one of NK-generating cytokines, in bone marrow cells. Phoslactomycin A and leustroducsin H, other specific inhibitors of PP2A, also augmented NK cell activity and inhibited lung metastasis, but a CTS analogue without inhibitory activity on PP2A and calyculin A, a dual inhibitor of PP1 and PP2A, did not. These results suggest that specific inhibition of PP2A can augment NK cells through upregulation of NK-generating cytokine and prophylaxis for pulmonary metastasis.
选择性增强自然杀伤（NK）细胞可抑制肿瘤转移，但尚未确定NK细胞激活的分子靶点。我们在此报告，细胞抑素（CTS）是一种新型的蛋白磷酸酶（PP）2A特异性抑制剂，可通过NK细胞的扩增和激活来抑制B16黑色素瘤肺转移。体内给予CTS可增加骨髓细胞中Flt-3配体（一种NK生成细胞因子）的mRNA表达。PP2A的其他特异性抑制剂磷雷霉素A和鲁司他汀H也增强了NK细胞活性并抑制了肺转移，但对PP2A无抑制活性的CTS类似物和PP1与PP2A的双重抑制剂毛喉素A则没有这种作用。这些结果表明，PP2A的特异性抑制可通过上调NK生成细胞因子来增强NK细胞，并预防肺转移。
