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Ramos cells carry a non-functional p53 and constitutively express the transcription factor, NF-κB (Nazari et al., 2011, Zand et al., 2008). There is much evidence to support the conclusion that the interruption of NF-κB activation promotes apoptosis in several hematological malignancies (Fabre et al., 2007). EP4 receptor activation in Ramos pikfyve inhibitor leads to decreased levels of phospho-IκBα and phospho-p105. However, the levels of total IκBα as well as of p105 were accumulated continuously, indicating that the NF-κB pathway is inhibited. Namely, one of the main steps in activation of NF-κB pathway is phosphorylation of the precursor molecules (e.g. p105) and inhibitory proteins (e.g. IκB) by the IKK complex. The phosphorylated p105 and IκBα molecules are subsequently ubiquitinated and proteolytically degraded by the proteasome. This leads to the release of NFκB, which translocates into the nucleus where it binds with the promoters target genes (Hayden and Ghosh, 2008, Wertz and Dixit, 2010). The reduction of phosphorylated protein forms of p105 and IκBα, which is not accompanied by their degradation, therefore indicates the inhibition of the NF-κB pathway. Of note, the decrease of phospho-p105 was immediately present, but afterwards a time-dependent normalization could be observed. This can be attributed to the fact that phosphorylation is a transient state and often fluctuates with time. Also, molecules have a different phosphorylation profile and affinity, which seems to be the case for p105 and IκBα. However, this was beyond the scope of this study. The mechanism of Pge1-OH that lead to the inhibition of the NF-κB pathway still needs to be elucidated, nonetheless it links the EP4 receptor-induced apoptosis of Ramos cells to modulation of NF-κB activity.The over-expression of proteins of the anti-apoptotic BCL-2 family members, like BCL-xL, provides a common mechanism through which cancer cells gain a survival advantage. Recent research has provided further evidence linking the over-expression of BCL-xL to lymphoma progression as well as to the observed resistance to a wide spectrum of chemotherapeutic agents seen in patients with B-cell lymphoma (Gaidano and Dalla-Favera, 1993, Li et al., 2008). We found that the decreased NF-κB activity, which was due to EP4 receptor activation, was accompanied by a reduction in the levels of BCL-xL expression in Ramos cells. This finding is not surprising, as the promoter region of the BCL-xL gene contains binding sites for NF-κB (Khoshnan et al., 2000). The inducible loss of anti-apoptotic BCL-2 family members is associated with the occurrence of apoptosis and, therefore, presents an attractive strategy for cancer therapy (Li et al., 2008). We have further hypothesized that EP4 receptor-mediated down-regulation of BCL-xL could enhance the toxicity of chemotherapeutic agents. In order to address this notion, we selected two frequently used chemotherapeutics, a proteasome inhibitor (bortezomib) and a DNA-damaging agent (doxorubicin), for which development of resistance has been reported (Dalton et al., 1989, Miller et al., 1991). Ramos cells were treated with various concentrations of doxorubicin or bortezomib in the presence or absence of the EP4 receptor agonist, Pge1-OH. It is noteworthy that p53 frequently mutates in B-cell Burkitt׳s lymphoma cells; therefore, Ramos cells should not be susceptible to p53-mediated apoptosis after doxorubicin treatment (Farrell et al., 1991). In most of the tumor cells, resistance to DNA inducing agents correlates with the activation of the NF-κB and loss of function of the p53 signaling pathway (Weston et al., 2004). Therefore, the suppression of NF-κB is one of the major strategies for the improvement of chemotherapy resistance in p53 mutant tumor cells (Yamagishi et al., 1997). As anticipated, Ramos cells resisted the chemo-preventive effect of doxorubicin. This resistance, surmounted by the addition of a relatively nontoxic concentration of Pge1-OH, revealed synergistic effects of Pge1-OH and doxorubicin on the decrease in the metabolic activity of Ramos cells. A study by Nazari et al. showed that doxorubicin in Ramos cells increased the phosphorylation of IκBα and caused subsequent NF-κB activation. Furthermore, co-treatment with compounds, which cause reduction of IκBα phosphorylation (e.g. hesperidin), lead to chemo-sensation to doxorubicin. We predict that EP4 has a similar mechanism of action in overcoming resistance to doxorubicin, since we also observed a decrease in phospho-IκBα levels if Pge1-OH was added. The same synergistic effects were observed using Pge1-OH and bortezomib. Among its many activities, bortezomib inhibits IκBα degradation with the subsequent inhibition of constitutive NF-κB, resulting in the apoptosis of cells (Zou et al., 2007). The dual inhibition of NF-κB activity by Pge1-OH and bortezomib therefore results in synergistically increased cell death.