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Distinct inhibitory efficiency of siRNAs and DNAzymes to β1 integrin subunit in blocking tumor growth

100%

Wiktorska M., Sacewicz-Hofman I., Stasikowska-Kanicka O., Danilewicz M., Niewiarowska J.

Acta Biochimica Polonica

2013

vol. 60

issue 1

77-82

Receptors of the β1 integrin family are involved in many tumor-promoting activities. There are several approaches currently used to control integrin activity, and thus to potentially restrain tumor metastasis and angiogenesis. In this study, we compared inhibitory efficiencies of siRNA and DNAzymes against the β1 integrin subunit (DEβ1), in a mouse xenograft model. Both inhibitors were used under their most favorable conditions, in terms of concentrations, incubation time and lack of cytotoxic effects. Transfection of siRNAβ1 or DEβ1 remarkably inhibited the growth of both PC3 and HT29 colon cancer cells in vitro, and decreased their capability of initiating tumor formation in the mouse xenograft model. siRNAβ1 appeared to be slightly more efficient than DEβ1 when tested in vitro, however it was comparably less proficient in blocking the tumor growth in vivo. We conclude the DNAzyme, due to its greater resistance to degradation in extra- and intracellular compartments, to be a superior inhibitor of tumor growth in long lasting experiments in vivo when compared to siRNA, while the latter seems to be more efficient in blocking β1 expression during in vitro experiments using cell cultures.

DNAzyme as an efficient tool to modulate invasiveness of human carcinoma cells

100%

Wiktorska M., Papiewska-Pająk I., Okruszek A., Sacewicz-Hofman I., Niewiarowska J.

Acta Biochimica Polonica

2010

vol. 57

issue 3

269-275

In this study we evaluated efficiency of DNAzymes to modulate motility of cancer cells, an important factor in the progression and metastasis of cancers. For this purpose we targeted β1 integrins that are predominant adhesive receptors in various carcinoma cell lines (CX1.1, HT29, LOVO, LS180, PC-3). To evaluate invasiveness of cancer cells, we used a transwell migration assay that allowed analyzing chemotactic migration of colon carcinoma cell lines across an ECM-coated membrane. Their adhesive properties were also characterized by the analysis of adhesion to fibronectin, laminin and collagen. In addition, the expression of major integrin subunits, selected intact β1 integrins, and other adhesive receptors (ICAM, E-selectin, uPAR) was analyzed by flow cytometry. Inhibition of β1 integrin expression by DNAzyme to β1 mRNA almost abolished the invasiveness of the CX1.1, HT29, LS180, LOVO and PC-3 cells in vitro. These data show that DNAzymes to β1 integrin subunit can be used to inhibit invasiveness of carcinoma cells.

Functional characteristic of PC12 cells with reduced microsomal glutathione transferase 1

73%

Sobczak M., Boczek T., Ferenc B., Taha J., Kozaczuk A., Wiktorska M., Sacewicz-Hofman I., Niewiarowska J., Zylinska L.

Acta Biochimica Polonica

2010

vol. 57

issue 4

589-596

Microsomal glutathione transferase 1 (MGST1) possesses glutathione transferase and peroxidase activities and is active in biotransformation of xenobiotics and in defense against oxidative stress. To assess MGST1 role in the development and functioning of PC12 cells, we constructed a cell line with reduced MGST1 (PC12_M). Real-time PCR and immunoblot assays showed MGST1 expression lowered to 60 % and immunocytochemical analyses demonstrated an altered concentration and distribution of the enzyme. PC12_M cells revealed a larger tendency to grow in clusters, weaker adhesion, irregular shape of bodies, short neurite outgrowth and higher percentage of necrotic cells (34 %). The total GSTs activity determined with non-specific substrate CDNB (1-chloro-2,4-dinitrobenzene) decreased by 15-20 %, whereas that with DCNB (2,4-dichloro-1-nitrobenzene), a substrate more specific for cytosolic GSTs, was similar to the one in control cells. This suggests that reduction of MGST1 cannot be compensated by other glutathione transferases. In PC12_M cells the total glutathione content was higher by 15-20 %, whereas the GSSG/GSH ratio was lower than in control cells. Moreover, the laminin-dependent migration rate was much faster in control cells than in PC12_M, suggesting some alterations in the metastatic potential of the line with suppressed MGST1. The amount of MAP kinases (p38, JNK, ERK1/2) was elevated in PC12_M cells but their phosphorylation level declined. Microarray analysis showed changed expression of several genes, which may be linked with differentiation and necrosis of PC12_M cells. Our data suggest that MGST1 could be an important regulator of PC12 cells development and might have significant effects on cell growth and proliferation, probably through altered expression of genes with different biological function.

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3 Acta Biochimica Polonica

1 2013

2 2010

3 Niewiarowska J.

3 Sacewicz-Hofman I.

3 Wiktorska M.

1 Boczek T.

1 Danilewicz M.

1 Ferenc B.

1 Kozaczuk A.

1 Okruszek A.

1 Papiewska-Pająk I.

1 Sobczak M.

1 Stasikowska-Kanicka O.

1 Taha J.

1 Zylinska L.

Search results

Distinct inhibitory efficiency of siRNAs and DNAzymes to β1 integrin subunit in blocking tumor growth

DNAzyme as an efficient tool to modulate invasiveness of human carcinoma cells

Functional characteristic of PC12 cells with reduced microsomal glutathione transferase 1