title: Inhibition of the CaM-kinases augments cell death in response to oxygen radicals and oxygen radical inducing cancer therapies in MCF-7 human breast cancer cells.
abstract: Many cancer treatments induce cell death through lethal oxidative stress. Oxidative stress also induces the activation of the calcium/calmodulin-dependent kinases (CaM-Ks), CaM-KII and CaM-KIV. In turn, the CaM-Ks are known to induce the activation of antiapoptotic signaling pathways, such as Akt, ERK, and NF-kappaB in many different cell types. The aim of this study was to determine the role of CaM-Kinases in resistance to hydrogen peroxide and three oxidative stress-inducing cancer therapies in MCF-7 breast cancer cells. We found that oxidative stress induced CaM-Kinase activity in MCF-7 breast cancer cells and that CaM-K inhibition increased hydrogen peroxide-induced cell death in MCF-7 human breast cancer cells. When MCF-7 cells were treated with doxorubicin, ionizing radiation, or photodynamic therapy in the presence of a CaM-K inhibitor a greater level of cell killing was observed than when cells were treated with doxorubicin, ionizing radiation, or photodynamic therapy alone. In support of this finding, CaM-K inhibition increased hydrogen peroxide-induced apoptosis in MCF-7 cells, as determined by increased number of apoptotic cells, DNA fragmentation, and PARP cleavage. Pharmacological and molecular inhibition indicated that CaM-KII was participating in hydrogen peroxide-induced ERK phosphorylation in breast cancer cells indicating a potential mechanism by which this sensitization occurs. This is the first time that CaM-K inhibition is reported to sensitize cancer cells to reactive oxygen intermediate inducing cancer treatments.
authors.affiliation: Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, North Carolina 27834, USA.
authors.forename: Oswaldo G
authors.initials: OG
authors.lastname: Rodriguez-Mora
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Lahair
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Evans
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Kovacs
authors.forename: Ron R
authors.initials: RR
authors.lastname: Allison
authors.forename: Claudio H
authors.initials: CH
authors.lastname: Sibata
authors.forename: Kawana S
authors.initials: KS
authors.lastname: White
authors.forename: James A
authors.initials: JA
authors.lastname: McCubrey
authors.forename: Richard A
authors.initials: RA
authors.lastname: Franklin
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000628:therapy; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D015151:Immunoblotting; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress; D010766:Phosphorylation / Q000187:drug effects; D010778:Photochemotherapy; D034741:RNA, Small Interfering / Q000494:pharmacology; D011839:Radiation, Ionizing; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; D016877:Oxidants; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D004317:Doxorubicin; D006861:Hydrogen Peroxide; C517596:CAMK1 protein, human; C517683:CAMK4 protein, human; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3