Based on the analysis of the expression of 440 cancer-related genes by the Human Cancer Oligo GEArray microarray, we noted an overall increase in gene expression and only a minimal number of downregulated see more genes after treatment with ATRA alone or with ATRA in combinations with CA or CX. These findings are not surprising with regard to known mechanisms of retinoid action: both RA and retinoids bind to the inducible nuclear retinoid receptors that function as transcriptional factors of genes with RA-responsive elements [18, 19]. Our results

in both cell lines clearly show the crucial role of the RET proto-oncogene in retinoid-induced cell differentiation in neuroblastoma cells. RET is overexpressed in both cell lines after the application of ATRA alone or in combination with CA or CX. However, these cell lines differ in their response sensitivity: RET expression is upregulated in SK-N-BE(2) by treatment

with 1 μM ATRA and its combinations with CA or CX, whereas 10 μM ATRA (alone or in combination) is needed for the overexpression of RET in SH-SY5Y cells. These findings are completely in accordance both with other experiments on RET overexpression after retinoid-induced cell differentiation in the same neuroblastoma cell lines [18] and with our previous results with regard to the difference in response sensitivity [17]. Moreover, RET overexpression is associated with neuronal differentiation LDK378 nmr and correlates with the expression of NF-200 [17, 20]. The other gene that is overexpressed in both cell lines after the application of ATRA alone or in combination with CA or CX is RHOC, which encodes selleck inhibitor a member of the Rho GTPase family. Proteins of this family, especially RhoA, Rac1 and Cdc24, are

known to play an important role in actin cytoskeleton remodeling, and they are also involved in the neurite outgrowth and remodeling during neuronal differentiation [21, 22]. Besides playing a role in the metastasis of some human cancers, namely of breast carcinomas [23], overexpression of the RhoC protein was detected in glial precursors during differentiation of fetal neuroepithelial cells [24]. The detected overexpression of RHOC in both cell lines after treatment, especially in a concentration-dependent manner after combined treatment with CX, suggests the possible participation of this molecule in retinoid-induced differentiation. In contrast, same changes in the expression of RHOA were observed only in SK-N-BE(2) cells treated with ATRA and CX. In SH-SY5Y cells, RHOA was overexpressed after treatment with 1 μM ATRA and especially with its combinations with CA, whereas the same effect for RHOC was detected after treatment with 10 μM ATRA in SK-N-BE(2) cells. These data are in accordance with the hypothesis that the expression and activity of RhoA, B, and C proteins in cancer cells may be altered in different ways [25].