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...

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Bibliographic Details
Published in:International immunopharmacology 2003-02, Vol.3 (2), p.179-188
Main Authors: Kawada, Manabu, Kawatsu, Masaji, Masuda, Tohru, Ohba, Shun-ichi, Amemiya, Masahide, Kohama, Takafumi, Ishizuka, Masaaki, Takeuchi, Tomio
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Antineoplastic Agents - pharmacology
Biological and medical sciences
Chemotherapy
Cytokines
Cytokines - genetics
Enzyme Inhibitors - pharmacology
Female
Gene Expression Regulation - drug effects
Killer Cells, Natural - drug effects
Lymphocyte Activation - drug effects
Medical sciences
Mice
Mice, Inbred BALB C
Mice, SCID
Neoplasm Metastasis - prevention & control
NK cells
Organophosphates - pharmacology
Pharmacology. Drug treatments
Phosphoprotein Phosphatases - antagonists & inhibitors
Phosphoprotein Phosphatases - physiology
Protein Phosphatase 2
Protein phosphatases
Pyrones - pharmacology
RNA, Messenger - analysis
Tumor immunity
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Summary: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.
ISSN:1567-5769
1878-1705
DOI:10.1016/S1567-5769(02)00231-X