title: Protein kinase CK2 inhibition induces cell death via early impact on mitochondrial function.
abstract: CK2 (official acronym for casein kinase 2 or II) is a potent suppressor of apoptosis in response to diverse apoptotic stimuli-thus its molecular downregulation or activity inhibition results in potent induction of cell death. CK2 downregulation is known to impact mitochondrial apoptotic circuitry but the underlying mechanism(s) remain unclear. Utilizing prostate cancer cell lines subjected to CK2-specific inhibitors which cause loss of cell viability, we have found that CK2 inhibition in cells causes rapid early decrease in mitochondrial membrane potential (Δψm). Cells treated with the CK2 inhibitors TBB (4,5,6,7-tetrabromobenzotriazole) or TBCA (tetrabromocinnamic acid) demonstrate changes in Δψm which become apparent within 2 h, that is, significantly prior to evidence of activation of other mitochondrial apoptotic signals whose temporal expression ensues subsequent to loss of Δψm. Further, we have demonstrated the presence of CK2 in purified mitochondria and it appears that the effect on Δψm evoked by inhibition of CK2 may involve mitochondrial localized CK2. Results also suggest that alterations in Ca(2+) signaling may be involved in the CK2 mediated regulation of Δψm and mitochondrial permeability. Thus, we propose that a key mechanism of CK2 impact on mitochondrial apoptotic circuitry and cell death involves early loss of Δψm which may be a primary trigger for apoptotic signaling and cell death resulting from CK2 inhibition.
authors.affiliation: Cellular and Molecular Biochemistry Research Laboratory (151), Minneapolis Veterans Affairs Health Care System, Minneapolis, Minnesota, 55417; Department of Laboratory Medicine and Pathology, University of Minnesota School of Medicine, Minneapolis, MN, 55455; Department of Biochemistry and Molecular Biology, Army Medical College, National University of Sciences and Technology, Islamabad, Pakistan.
authors.forename: Fatima
authors.initials: F
authors.lastname: Qaiser
authors.forename: Janeen H
authors.initials: JH
authors.lastname: Trembley
authors.forename: Betsy T
authors.initials: BT
authors.lastname: Kren
authors.forename: Jing-Jiang
authors.initials: JJ
authors.lastname: Wu
authors.forename: A Khaliq
authors.initials: AK
authors.lastname: Naveed
authors.forename: Khalil
authors.initials: K
authors.lastname: Ahmed
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D020013:Calcium Signaling; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002374:Catalase / Q000378:metabolism; D045744:Cell Line, Tumor; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D014230:Triazoles / Q000494:pharmacology*
chemical_list: C405354:4,5,6,7-tetrabromobenzotriazole; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D014230:Triazoles; D004533:Egtazic Acid; D002374:Catalase; D047390:Casein Kinase II; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid
keywords: APOPTOSIS; MITOCHONDRIAL MEMBRANE POTENTIAL; MITOCHONDRIAL PERMEABILITY TRANSITION; PROSTATE CANCER; SIGNALING