Raf-1 kinase inhibitor protein modulation of the cellular response to chemotherapeutic drugs and PDE5 inhibitors.

摘要: RKIP was initially discovered as an endogenous inhibitor of the ERK and NF-κB pathways,and also shown to prolong activation GPCRs via inhibition GRK2 protein. Now increasing evidence has linked a metastases suppressing chemo-sensitising role in cancer cells.The effect investigated colon carcinoma cell line using variety chemotherapeutic agents from conventional newer targeted therapies. Initial results suggested that modulation drug response at level apoptosis; there did not appear be great observable effects proliferative cycle distribution cells after treatment with selected agents. Apoptosis by occurred doxorubicin, FasL, paclitaxel TRAIL. TRAIL-treated displayed increased death levels of within were increased. In contrast, FasL paclitaxel-treated scaffold-like levels cell; WT RKIP-expressing being more sensitive paclitaxel-induced apoptosis than low or high cells. There no 5-FU, cisplatin etoposide-induced apoptosis RKIP. Indeed, these three induce this line. RKIP chemo-sensitivity never been before is first time doxorubicin FasL-induced modulated Further, it here, for time, chemotherapy-induced can change depending upon cytotoxic employed treatment. TRAIL both members TNF super-family, further analysis due distinctive responses observed consequence cell. treatment, most TRAIL administration. Increased sensitivity appeared involve up-regulation DR5 receptor; down-regulation anti-apoptotic molecule Bcl-xl; pIKK which activates pathway; TRAF2 activate pathway. Whether directly interacts molecules unknown however bind upstream activators pathway another TRAF subtype TRAF6. YY1 expression evident but unchanged altered. The FasL-treated decreased increased; possible behaving pro- line. Thus may have prevented cells. The TRAF6, RKIP, having highest TRAF6 expression. This was also case transcriptional regulator YY1, thus YY1 pro-apoptotic-like manner cells. TRAF2 FasL-administered regardless cell. Overall, appears differential adaptor proteins responsible contrasting low, Utilisation particular adaptors combinations Fas receptors account roles pathway, recruitment other dependent stimulus. How affects requires investigation, are exciting novel, strengthen surrounding chemosensitivity. On note, PDE5 PF-3717842, therefore investigation inhibitors sildenafil citrate vardenafil on examined. The compared migration locostatin inhibit prevent RKIP-Raf-1 interaction. With TPA EGF stimulation, act consistent its known function inhibitor. citrate displayed similar trend locostatin, although their potent. It strong B-Raf over-shadowing subtle treatments. Under growth conditions, behave nor citrate. various cascades impinging overshadowing effects, resulting off-target (RKIP-unrelated) drugs. In summary, becoming increasingly avenue research consistently yielding new interesting interactions Understanding elucidating intriguing protein will only strengthen our knowledge signal transduction regulation modulation, provide source therapy means manipulation resistance.