CX-4945: the Protein Kinase CK2 Inhibitor and Anti-cancer Drug Shows Anti-fungal Activity

Overview

Journal Mol Cell Biochem

Publisher Springer

Specialty Biochemistry

Date 2017 May 15

PMID 28501934

Citations 6

Authors

Maciej Maslyk

Monika Janeczko

Aleksandra Martyna

Konrad Kubinski

Affiliations

Soon will be listed here.

Abstract

CX-4945 is a selective inhibitor of protein kinase CK2 exhibiting clinical significance. Its antitumor properties arise from the abrogation of CK2-mediated pro-survival cellular pathways. The presented data reveal the influence of CX-4945 on the growth of yeast cells showing variable potency against Saccharomyces cerevisiae deletion strains with different contents of CK2 subunits. The catalytic subunit CK2α appears to sensitize yeast to the CX-4945 action. Moreover, the compound suppresses hyphal growth and cell adhesion of Candida albicans, thereby abolishing some hallmarks of invasiveness of the pathogen. It is known that cancer patients are more prone to fungal infections. Our data unveil the dual-activity of CX-4945; when used in anti-cancer therapy, it may simultaneously prevent cancer-associated candidiasis.

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References

KREBS E . The growth of research on protein phosphorylation. Trends Biochem Sci. 1994; 19(11):439. DOI: 10.1016/0968-0004(94)90125-2. View

Janeczko M, Maslyk M, Kubinski K, Golczyk H . Emodin, a natural inhibitor of protein kinase CK2, suppresses growth, hyphal development, and biofilm formation of Candida albicans. Yeast. 2017; 34(6):253-265. DOI: 10.1002/yea.3230. View

Lo H, Kohler J, DiDomenico B, Loebenberg D, Cacciapuoti A, Fink G . Nonfilamentous C. albicans mutants are avirulent. Cell. 1997; 90(5):939-49. DOI: 10.1016/s0092-8674(00)80358-x. View

Domanska K, Zielinski R, Kubinski K, Sajnaga E, Maslyk M, Bretner M . Different properties of four molecular forms of protein kinase CK2 from Saccharomyces cerevisiae. Acta Biochim Pol. 2005; 52(4):947-51. View

Glover 3rd C . On the physiological role of casein kinase II in Saccharomyces cerevisiae. Prog Nucleic Acid Res Mol Biol. 1998; 59:95-133. DOI: 10.1016/s0079-6603(08)61030-2. View

Manning G, Whyte D, Martinez R, Hunter T, Sudarsanam S . The protein kinase complement of the human genome. Science. 2002; 298(5600):1912-34. DOI: 10.1126/science.1075762. View

Lozeman F, Litchfield D, Piening C, Takio K, Walsh K, KREBS E . Isolation and characterization of human cDNA clones encoding the alpha and the alpha' subunits of casein kinase II. Biochemistry. 1990; 29(36):8436-47. DOI: 10.1021/bi00488a034. View

Mayer F, Wilson D, Hube B . Candida albicans pathogenicity mechanisms. Virulence. 2013; 4(2):119-28. PMC: 3654610. DOI: 10.4161/viru.22913. View

Litchfield D . Protein kinase CK2: structure, regulation and role in cellular decisions of life and death. Biochem J. 2002; 369(Pt 1):1-15. PMC: 1223072. DOI: 10.1042/BJ20021469. View

10.

Hasan F, Xess I, Wang X, Jain N, Fries B . Biofilm formation in clinical Candida isolates and its association with virulence. Microbes Infect. 2009; 11(8-9):753-61. PMC: 2715444. DOI: 10.1016/j.micinf.2009.04.018. View

11.

Pierre F, Chua P, OBrien S, Siddiqui-Jain A, Bourbon P, Haddach M . Pre-clinical characterization of CX-4945, a potent and selective small molecule inhibitor of CK2 for the treatment of cancer. Mol Cell Biochem. 2011; 356(1-2):37-43. DOI: 10.1007/s11010-011-0956-5. View

12.

Fanning S, Mitchell A . Fungal biofilms. PLoS Pathog. 2012; 8(4):e1002585. PMC: 3320593. DOI: 10.1371/journal.ppat.1002585. View

13.

Konstantinidou N, Morrissey J . Co-occurence of filamentation defects and impaired biofilms in Candida albicans protein kinase mutants. FEMS Yeast Res. 2015; 15(8). DOI: 10.1093/femsyr/fov092. View

14.

Guerra B, Issinger O . Protein kinase CK2 in human diseases. Curr Med Chem. 2008; 15(19):1870-86. DOI: 10.2174/092986708785132933. View

15.

Sajnaga E, Kubinski K, Szyszka R . Catalytic activity of mutants of yeast protein kinase CK2alpha. Acta Biochim Pol. 2008; 55(4):767-76. View

16.

Siddiqui-Jain A, Drygin D, Streiner N, Chua P, Pierre F, OBrien S . CX-4945, an orally bioavailable selective inhibitor of protein kinase CK2, inhibits prosurvival and angiogenic signaling and exhibits antitumor efficacy. Cancer Res. 2010; 70(24):10288-98. DOI: 10.1158/0008-5472.CAN-10-1893. View

17.

Tripodi F, Cirulli C, Reghellin V, Marin O, Brambilla L, Schiappelli M . CK2 activity is modulated by growth rate in Saccharomyces cerevisiae. Biochem Biophys Res Commun. 2010; 398(1):44-50. DOI: 10.1016/j.bbrc.2010.06.028. View

18.

Meggio F, Pinna L . One-thousand-and-one substrates of protein kinase CK2?. FASEB J. 2003; 17(3):349-68. DOI: 10.1096/fj.02-0473rev. View

19.

Drygin D, Ho C, Omori M, Bliesath J, Proffitt C, Rice R . Protein kinase CK2 modulates IL-6 expression in inflammatory breast cancer. Biochem Biophys Res Commun. 2011; 415(1):163-7. DOI: 10.1016/j.bbrc.2011.10.046. View

20.

Ramirez-Garcia A, Rementeria A, Aguirre-Urizar J, Moragues M, Antoran A, Pellon A . Candida albicans and cancer: Can this yeast induce cancer development or progression?. Crit Rev Microbiol. 2014; 42(2):181-93. DOI: 10.3109/1040841X.2014.913004. View