casein-kinase-ii and Rhabdomyosarcoma

For the first time, a review article focuses exclusively on the role of the protein kinase CK2 in mono- and poly-nucleated mammalian skeletal muscle cells. While CK2, a pleiotropic serine/threonine kinase was originally thought to phosphorylate mainly casein, later evidence found glycogen phosphorylase and glycogen synthase also to be a target, linking the enzyme to muscle biology. Indeed, recent studies have shown that CK2 is involved in many different steps in the biology of striated skeletal muscle, such as myogenesis and homeostasis in the adult muscle, and even at the neuromuscular junctions, the points of contact between the muscle fibers and the motor nerves end. Next to the role of CK2 in muscle physiology, this review also highlights the contribution of CK2 in muscle pathologies, such as muscle tumors and myopathies.

Topics: Animals; Casein Kinase II; Humans; Muscle Development; Muscle Fibers, Skeletal; Muscle, Skeletal; Neuromuscular Junction; Rhabdomyosarcoma

Topics: Casein Kinase II; Humans; Publishing; Rhabdomyosarcoma; Tumor Cells, Cultured

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis via the death receptors DR4 and DR5 in transformed cells in vitro and exhibits potent antitumor activity in vivo with minor side effects. Protein kinase casein kinase II (CK2) is increased in response to diverse growth stimuli and is aberrantly elevated in a variety of human cancers. Rhabdomyosarcoma tumors are the most common soft-tissue sarcoma in childhood. In this investigation, we demonstrate that CK2 is a key survival factor that protects tumor cells from TRAIL-induced apoptosis. We have demonstrated that inhibition of CK2 phosphorylation events by 5,6-dichlorobenzimidazole (DRB) resulted in dramatic sensitization of tumor cells to TRAIL-induced apoptosis. CK2 inhibition also induced rapid cleavage of caspase-8, -9, and -3, as well as the caspase substrate poly(ADP-ribose) polymerase after TRAIL treatment. Overexpression of Bcl-2 protected cells from TRAIL-induced apoptosis in the presence of the CK2 inhibitor. Death signaling by TRAIL in these cells was Fas-associated death domain and caspase dependent because dominant negative Fas-associated death domain or the cowpox interleukin 1beta-converting enzyme inhibitor protein cytokine response modifier A prevented apoptosis in the presence of DRB. Analysis of death-inducing signaling complex (DISC) formation demonstrated that inhibition of CK2 by DRB increased the level of recruitment of procaspase-8 to the DISC and enhanced caspase-8-mediated cleavage of Bid, thereby increasing the release of the proapoptotic factors cytochrome c, HtrA2/Omi, Smac/DIABLO, and apoptosis inducing factor (AIF) from the mitochondria, with subsequent degradation of X-linked inhibitor of apoptosis protein (XIAP). To further interfere with CK2 function, JR1 and Rh30 cells were transfected with either short hairpin RNA targeted to CK2alpha or kinase-inactive CK2alpha (K68M) or CK2alpha' (K69M). Data show that the CK2 kinase activity was abrogated and that TRAIL sensitivity in both cell lines was increased. Silencing of CK2alpha expression with short hairpin RNA was also associated with degradation of XIAP. These findings suggest that CK2 regulates TRAIL signaling in rhabdomyosarcoma by modulating TRAIL-induced DISC formation and XIAP expression.

Topics: Adaptor Proteins, Signal Transducing; Apoptosis; Apoptosis Regulatory Proteins; Benzimidazoles; Casein Kinase II; Caspase 6; Caspase 8; Caspases; Cell Line, Tumor; Drug Resistance, Neoplasm; Fas-Associated Death Domain Protein; Green Fluorescent Proteins; Humans; Isoenzymes; Membrane Glycoproteins; Mitochondria; Mutation, Missense; Phosphorylation; Protein Subunits; Proteins; Proto-Oncogene Proteins c-bcl-2; Receptors, TNF-Related Apoptosis-Inducing Ligand; Receptors, Tumor Necrosis Factor; Rhabdomyosarcoma; RNA, Small Interfering; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand; Transfection; Tumor Necrosis Factor-alpha; X-Linked Inhibitor of Apoptosis Protein