Hygrolidin induces p21 expression and abrogates cell cycle progression at G1 and S phases.
Hygrolidin family antibiotics showed selective cytotoxicity against both cyclin E- and cyclin A-overexpressing cells. Among them, hygrolidin was the most potent and inhibited growth of solid tumor-derived cell lines such as DLD-1 human colon cancer cells efficiently more than that of hematopoietic tumor cells and normal fibroblasts. FACS analysis revealed that hygrolidin increased cells in G1 and S phases in DLD-1 cells. While hygrolidin decreased amounts of cyclin-dependent kinase (cdk) 4, cyclin D, and cyclin B, it increased cyclin E and p21 levels. Hygrolidin-induced p21 bound to and inhibit cyclin A-cdk2 complex more strongly than cyclin E-cdk2 complex. Furthermore, hygrolidin was found to increase p21 mRNA in DLD-1 cells, but not in normal fibroblasts. Thus, hygrolidin inhibited tumor cell growth through induction of p21. In respect to p21 induction, inhibition of vacuolar-type (H+)-ATPase by hygrolidin was suggested to be involved.
Kawada
Manabu
M
Institute for Chemotherapy, Microbial Chemistry Research Foundation, 18-24 Miyamoto, Numazu-shi, Shizuoka-ken 410-0301, Japan.
Usami
Ihomi
I
Ohba
Shun
S
Someno
Tetsuya
T
Kim
Jin
J
Hayakawa
Yoichi
Y
Nose
Kiyoshi
K
Ishizuka
Masaaki
M
D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D042846:CDC2-CDC28 Kinases; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D019925:Cyclin A / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000096:biosynthesis* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016193:G1 Phase / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D018942:Macrolides; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012334:RNA, Neoplasm / Q000096:biosynthesis; D051381:Rats; D016196:S Phase / Q000187:drug effects; D014407:Tumor Cells, Cultured; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors
D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; C493958:Cdkn1a protein, rat; D019925:Cyclin A; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D018942:Macrolides; D012334:RNA, Neoplasm; C465999:hygrolidin; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495892:Cdk2 protein, rat; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D025262:Vacuolar Proton-Translocating ATPases