Monensin-mediated growth inhibition of SNU-C1 colon cancer cells via cell cycle arrest and 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 solid tumor 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 SNU-C1 cells, monensin decreased the levels of CDK2, CDK4, CDK6, cyclin D1 and cyclin A proteins. While p27 was increased by monensin, p21 was not. In addition, monensin markedly enhanced the binding of p27 with CDK2, CDK4 and CDK6. Furthermore, the activities of CDK2-, CDK4- and CDK6-associated kinase were reduced in association with hypophosphorylation of Rb protein. Monensin also induced apoptosis in solid tumor cells. Apoptotic process of SNU-C1 cells was associated with the changes of Bax, caspase-3 and mitochondria transmembrane potential (deltapsim). Taken together, these results demonstrated for the first time that monensin inhibited the growth of solid tumor cells, especially SNU-C1 cells, via cell cycle arrest and apoptosis.
Park
Woo Hyun
WH
Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
Kim
Eun Shil
ES
Jung
Chul Won
CW
Kim
Byoung Kook
BK
Lee
Young Yiul
YY
D000230:Adenocarcinoma / Q000473:pathology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000473:pathology; D042846:CDC2-CDC28 Kinases; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000473:pathology*; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006367:HeLa Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D007476:Ionophores / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D008985:Monensin / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D016160:Retinoblastoma Protein / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000473:pathology; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D018797:Cell Cycle Proteins; D007476:Ionophores; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; D050760:Cyclin-Dependent Kinase Inhibitor p27; D008985:Monensin; D012964:Sodium; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases