The IκB kinase NFB signalling pathway can also be typically altered in tumours and NFB can affect all six hallmarks of cancer through the transcriptional activation of genes linked with cell proliferation, angiogenesis, metastasis, tumour promotion, inflammation and suppression of apoptosis. PI3K and NF kB signalling pathways are functionally linked, staying NF kB potentially activated by Akt kinase. Our outcomes demonstrate that, similarly to PIK3R2, NFKB1 gene expression is down regulated by D6 in melanoma cells, but it is unclear irrespective of whether this could be because of the PI3K Akt signalling repression. Deeper investigations should be made to shed light on this molecular event. Nonetheless, it really is exciting to underline that PI3K and NF kB pathways are both concerned in curcumin anti tumour action and inhibition of NF kB activation may possibly ac count for curcumin efficacy on cancer cells and, specif ically, on human melanoma cells.
Like a consequence, it is probably the curcumin analogue D6 shares some mechanisms of action with its normal compound, staying even more effective in inhibiting tumour cells development. It truly is noteworthy that neither PIK3R2 nor NFKB1 genes ex pression was modulated in D6 treated usual fibroblasts. Based mostly on these concerns, we will postulate selleck chemical that PI3K and NF kB signalling down regulation is strongly associated with the anticancer action of D6 on melanoma cells. A more consideration could be accomplished about a possible re lationship in between NFKB1 below expression and p53 sig nalling up regulation. An extreme crosstalk exists among these two transcription factors that activate the expression of genes with opposite functions.
They may be certainly competi tors to the transcriptional coactivator our site p300 CBP and, based on which of them recruits this protein, various downstream pathways will be acti vated, leading to either cell proliferation or growth arrest and apoptosis. To this regard, a latest report by Sen and colleagues demonstrated that curcumin re verses doxorubicin resistance in breast cancer by inhibiting NFB activation and hence rescuing p300 coactivator, which in turn turns into offered towards the p53 transcription element, and finally allows p53 dependent transactivation of proapoptotic proteins this kind of as Bax, PUMA and Noxa. Based mostly on these observations down regulation of NFB by D6 would make the coactivator p300 available for recruit ment by p53, as a result favouring transactivation of its target genes that triggers antiproliferative and proapoptotic activ ity.
This might be an extremely exciting function of D6 mainly because its potentiality to each inhibit NFB and, on the identical time, rescue p53 signalling may very well be exploited either for direct therapeutic interventions towards cancer, but additionally in mixed therapies so that you can sensitize resistant cancer cells to chemotherapeutic agents which will stimulate apop tosis by inducing DNA damages and triggering p53 apoptotic signals. In summary, based on gene expression profile evaluation re sults, we will speculate that unique molecular mecha nisms may perhaps contribute to the anticancer impact of D6 in melanoma cells, i the induction of a cell worry response that triggers the ER worry mediated apoptosis pathway, ii the up regulation of p53 signalling, which promotes p21 and GADD45 dependent cell cycle arrest at the same time as mito chondrial apoptosis based mostly on Noxa over expression, iii the down modulation of a number of growth signals, like each PI3K and NF kB pathways, and c kit receptor.