Specific inhibitors of protein phosphatase 2A inhibit tumor metastasis through augmentation of natural killer cells.

Abstract

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.

• Authors: Manabu Kawada, Masaji Kawatsu, Tohru Masuda, Shun-ichi Ohba, Masahide Amemiya, Takafumi Kohama, Masaaki Ishizuka, Tomio Takeuchi
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 3 Issue 2 Pg. 179-88 (Feb 2003) ISSN: 1567-5769 [Print] Netherlands
• PMID: 12586599 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2003 Elsevier Science B.V.

Chemical References

• Antineoplastic Agents
• Cytokines
• Enzyme Inhibitors
• Organophosphates
• Pyrones
• RNA, Messenger
• cytostatin
• Phosphoprotein Phosphatases
• Protein Phosphatase 2

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cytokines (genetics)
• Enzyme Inhibitors (pharmacology)
• Female
• Gene Expression Regulation (drug effects)
• Killer Cells, Natural (drug effects)
• Lymphocyte Activation (drug effects)
• Mice
• Mice, Inbred BALB C
• Mice, SCID
• Neoplasm Metastasis (prevention & control)
• Organophosphates (pharmacology)
• Phosphoprotein Phosphatases (antagonists & inhibitors, physiology)
• Protein Phosphatase 2
• Pyrones (pharmacology)
• RNA, Messenger (analysis)