[Casein kinase 2, the versatile regulator of cell survival].

Casein kinase 2 (CK2), a highly conservative, multifunctional serine/threonine protein kinase, is critically important for the regulation of a plethora of processes in eukaryotes, such as cell proliferation, differentiation and death. CK2 is expressed in all tissues; in particular, its amount and activity are elevated in tumor cells. Unlike many regulatory proteins CK2 permanently adopts an active conformation. Of the utmost importance are the anti-apoptotic functions of CK2. This protein kinase is capable of regulating cell survival at multiple levels including DNA repair, NF-kappaB, Wnt, PI3K/Akt and JAK-STAT signaling cascades, chaperones, activation of anti-apoptotic proteins and down-regulation of pro-apoptotic counterparts, in particular, caspases. The versatility of CK2-mediated phosphorylation ensures the survival of tumor cells exposed to stimuli that differ in the origin and mechanisms of cytotoxicity. This manifold mode of CK2-dependent survival makes this enzyme an important target for antitumor therapy.

[Stimulation of differentiation of LIM 1215 large intestinal tumor cells during expression of the p53 exogenous antioncogene or the activated ras oncogene]. / Stimuliatsiia differentsirovki kletok raka tolstoi kishki linii LIM 1215 pri ékspressii ékzogennogo antionkogena p53 ili aktivirovannogo onkogena ras.

The ability of exogenous p53 tumor-suppressor and activated N-PAS oncogene to influence differentiation state of human colon carcinoma LIM 1215 cells and their derivatives with acquired resistance to actinomycin D or methotrexate was analysed Introduction of retroviral construct expressing human wild-type (wt) p53 into LIM 1215 cells induced electron microscopic manifestations of enterocytic differentiation, i.e. caused an increase in the numbers of cells with microvilli, desmosomes and glandular-like lumens. Mutations at codons 248 or 273, the most frequent p53 changes in primary colorectal cancer, partially abrogated the ability of p53 to stimulate differentiation of LIM 1215 cells. Human M-PASasp12 showed stronger stimulation of cell differentiation as compared to p53wt. Especially high proportion (> 80%) of cells possessing pronounced manifestations of columnar enterocytic differentiation was observed after introduction of PAS-expressing construct into methotrexate-resistant LIM 1215 cell subline that originally demonstrated higher maturation than parental cell line. In cell subline with two introduced genes, activated PAS and mutant p53His273, the number of differentiated cells was similar to that observed in cell culture containing only PAS-construct. However, these two sublines differed in the quantity of desmosomes as well as in carcino-embryonic antigen (CEA) expression. Comparison of expression of different electron microscopic features of cell differentiation and CEA expression in cell sublines selected for methotrexate-resistance and/or expressing exogenous constructs allows to suppose that p53 tumor-suppressor, PAS oncogene and dhfr gene amplification may lead to somewhat distinct differentiation states.

[The differentiation of tumor cells of the human large intestine during the acquisition of multiple drug resistance]. / Differentsirovka kletok opukholei tolstoi kishki cheloveka pri priobretenii mnozhestvennoi lekarstvennoi ustoichivosti.

By selection in the medium containing increasing actinomycin D concentrations two sublines with acquired multidrug resistance (MDR) caused by P-glycoprotein (P170) overproduction were isolated. The obtained cell lines as well as parent cells grow in vitro as morphologically organized aggregates, so-called organoids. Comparative electron microscopic study of sensitive and drug resistant organoids has shown that the development of MDR was accompanied by the enhancement of the tumour cell differentiation: the percentage of differentiated cells, the extent of their maturity, and the quantity of lumens were higher in MDR organoids than in parent cell line. The size of glandular structures in resistant organoids was also enlarged. Possible mechanisms of observed phenomenon are discussed.