Monensin inhibits the growth of renal cell carcinoma cells via cell cycle arrest or apoptosis.
Previously, we showed that monensin, Na+ ionophore, potently inhibited the growth of acute myelogenous leukemia and lymphoma cells. Here, we demonstrate that monensin inhibited the proliferation of renal cell carcinoma cells with IC50 of about 2.5 micro M. Monensin induced a G1 or a G2-M phase arrest in these cells. When we examined the effects of this drug on ACHN cells, monensin decreased the levels of CDK2, CDK6, cdc2, cyclin A and cyclin B1 proteins. p21 and p27 proteins were increased by monensin. In addition, monensin markedly enhanced the binding of p21 with CDK2 and the binding of p27 with CDK6. Furthermore, the activities of CDK2- and CDK6-associated kinase were reduced in association with hypophosphorylation of Rb protein. Monensin also induced the apoptosis in several renal cell carcinoma cells. Apoptotic process of Caki-2 cells was associated with the changes of Bcl-2, Bcl-XL, caspase-9, caspase-3, caspase-7 proteins as well as mitochondria transmembrane potential (DeltaPsim) loss. Taken together, these results demonstrate for the first time that monensin inhibits the growth of renal cell carcinoma cells via cell cycle arrest or apoptosis.
Park
Woo Hyun
WH
Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Jung
Chul Won
CW
Park
Joon Oh
JO
Kim
Kihyun
K
Kim
Won Seog
WS
Im
Young Hyuck
YH
Lee
Mark H
MH
Kang
Won Ki
WK
Park
Keunchil
K
D000935:Antifungal Agents / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D042846:CDC2-CDC28 Kinases / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle; D002455:Cell Division; D002460:Cell Line; D045744:Cell Line, Tumor; D051357:Cyclin-Dependent Kinase 2; D051361:Cyclin-Dependent Kinase 6; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016193:G1 Phase; D016195:G2 Phase; D006801:Humans; D020128:Inhibitory Concentration 50; D007476:Ionophores / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000188:drug therapy*; D008840:Microfilament Proteins / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008985:Monensin / Q000494:pharmacology*; D009124:Muscle Proteins; D010766:Phosphorylation; D011233:Precipitin Tests; D016160:Retinoblastoma Protein / Q000378:metabolism; D012964:Sodium / Q000378:metabolism
D000935:Antifungal Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D007476:Ionophores; D008840:Microfilament Proteins; D009124:Muscle Proteins; D016160:Retinoblastoma Protein; C058992:Tagln protein, mouse; D008985:Monensin; D012964:Sodium; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495911:CDK6 protein, human; D051357:Cyclin-Dependent Kinase 2; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases; D020169:Caspases