Specific inhibitors of protein phosphatase 2A inhibit tumor metastasis through augmentation of natural killer cells.
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.
Kawada
Manabu
M
Institute for Chemotherapy, Microbial Chemistry Research Foundation, 18-24 Miyamoto, Numazu, Shizuoka 410-0301, Japan.
Kawatsu
Masaji
M
Masuda
Tohru
T
Ohba
Shun-ichi
S
Amemiya
Masahide
M
Kohama
Takafumi
T
Ishizuka
Masaaki
M
Takeuchi
Tomio
T
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007694:Killer Cells, Natural / Q000187:drug effects*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D010755:Organophosphates / Q000494:pharmacology*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000502:physiology; D054648:Protein Phosphatase 2; D011753:Pyrones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis
D000970:Antineoplastic Agents; D016207:Cytokines; D004791:Enzyme Inhibitors; D010755:Organophosphates; D011753:Pyrones; D012333:RNA, Messenger; C088526:cytostatin; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2