Proteina quinasa

Biochimica et Biophysica Acta 1804 (2010) 499–504

Contents lists available at ScienceDirect

Biochimica et Biophysica Acta
j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / b b a p a p

Addiction to protein kinase CK2: A common denominator of diverse cancer cells?
Maria Ruzzene, Lorenzo A. Pinna ⁎
Department of Biological Chemistry and CNR Institute ofNeurosciences, University of Padova, and Venetian Institute of Molecular Medicine (VIMM), Padova, Italy

a r t i c l e

i n f o

a b s t r a c t
At variance with most oncogenic protein kinases whose malignancy is generally due to genetic alterations conferring constitutive activity, CK2 is a highly pleiotropic Ser/Thr protein kinase naturally endowed with constitutive activity and lackinggain-of-function mutants. Nonetheless CK2 is abnormally elevated in a wide variety of tumors and there is strong evidence that it operates as a cancer driver by creating a cellular environment favorable to neoplasia: notably, CK2 plays a global role as an anti-apoptotic and pro-survival agent, it enhances the multi-drug resistance (MDR) phenotype, it assists the chaperone machinery which protects the“onco-kinome” and it promotes neo-angiogenesis. Based on this scenario we propose that the implication of CK2 in neoplasia is an example of “non oncogene addiction”, i.e. over reliance of the perturbed cellular signaling network on high CK2 level for its own maintenance. Consistent with this, an ample spectrum of diverse types of cancer cells have been already shown to rely on high CK2 level for theirsurvival, as judged from their response to specific CK2 inhibitors and silencing of endogenous CK2 catalytic subunits. Remarkably, among these are cells whose cancer phenotype arises from the genetic alteration of oncokinases (e.g. Abl and Alk) different from CK2 and insensitive to the CK2 inhibitors used in those experiments. Based on these premises, CK2 could represent a “multi-purpose” targetfor the treatment of different kinds of tumors. © 2009 Elsevier B.V. All rights reserved.

Article history: Received 19 June 2009 Received in revised form 24 July 2009 Accepted 28 July 2009 Available online 6 August 2009 Keywords: CK2, casein kinase 2 (II) Signal transduction therapy Addiction Protein kinase inhibitors Cancer

1. Introduction A rising concept in molecular medicine is that mosthuman diseases are related to communication disorders, due to alterations in signaling pathways. This gave rise to the neologism Signal Transduction Therapy (STT) to denote strategies aimed at counteracting the pathological consequences of such alterations. Whenever applicable, protein kinases are the first choice targets in STT because they are enzymes, thus their catalytic activity can be readilyand effectively turned off by active site-directed inhibitors which are respectful of the overall conformation of the kinase. This latter, therefore, in its inhibited form, is acting as a dominant negative with respect to the active molecules thus contributing to the amplification of the inhibitory effect, and possibly accounting for the observation that sometimes the in vivo efficacy of the kinaseinhibitors is greater than it would be expected based on the degree of inhibition of the target kinase [1].

Abbreviations: ALCL, anaplastic large cell lymphoma; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CML, chronic myeloid leukemia; MDR, multi-drug resistance; MM, multiple myeloma; NF-kB, nuclear factor-kB; PDK1, 3′phosphoinositide-dependent kinase-1; PI3K,phosphatidylinositol-3 kinase; PIP2, phosphatidylinositide 4,5-diphosphate; PIP3, phosphatidylinositol 3,4,5-triphosphate; PML, promyelocytic leukemia gene; PTEN, phosphatase and tensin homolog deleted on chromosome 10; PTK, protein tyrosine kinase; STT, signal transduction therapy ⁎ Corresponding author. Department of Biological Chemistry, University of Padova, Viale G. Colombo, 3, 35121 Padova, Italy....