Though clear inhibition of pERK1 2 was detected in all cell lines, pMSK1 was only decreased in UT SCC40, which only showed an additive effect of MEK inhibition. Hence, these data suggest that the radiosensitizing effect Axitinib clinical trial of MEK inhibition is not regulated via MSK. Specific inhib ition of MSK will be necessary to further investigate the role of MSK in radioresistance in HNSCC. Interestingly, the cell line that showed synergism between MEK inhi bition and radiotherapy, also showed a synergistic effect of p38 inhibition. Also with this inhibitor no decrease of pMSK1 levels was observed. MEK and p38 both belong to the family of mitogen activated protein ki nases. Therefore, MEK and p38 may activate another common pathway that is important for survival after radiotherapy in UT SCC24A cells, for example both MEK and p38 can activate MNK1 and thereby regulate mRNA translation.
Surprisingly, increased pMEK1 2 levels were observed in all cell lines after MEK inhibition, Inhibitors,Modulators,Libraries and also p p38 was increased by p38 inhibition in the cell line that showed decreased survival after radiotherapy. Upregulation Inhibitors,Modulators,Libraries of pMEK1 2 after MEK inhibition has also been observed by Turke et al. and they attributed it to a negative feedback mechanism that activates an upstream signaling mol ecule. Indeed, we did observe decreased pERK1 2 levels indicating that MEK activity was decreased by the in hibitor despite increased pMEK1 2 levels. Accordingly, increased p p38 levels after p38 inhibition in the sen sitive cell line might indicate effective inhibition of p38 and Inhibitors,Modulators,Libraries its downstream pathways instead of increased activity of p38.
Members of the STAT family have been shown to be activated in epithelial tumors, including HNSCC, and are known to induce the transcription of genes involved in cell survival, proliferation and angiogenesis. Acti vation of STAT5 has also been shown to contribute to tumor growth and resistance to cisplatin and EGFR inhibition in HNSCC cell lines. However, it has not Inhibitors,Modulators,Libraries been previously described that STAT5 and STAT6 cor relate with radiosensitivity as we find in our study. An other member of the STAT family, STAT3, has been shown to be involved in resistance to radiotherapy. Hence, our results indicate that also other STAT members play an important role in radiosensitivity Inhibitors,Modulators,Libraries in HNSCC. This is also indicated by a study of Lesterhuis et al.
who observed a trend toward a shorter pro gression free survival for STAT6 expressing tumors in a cohort of HNSCC patients treated with radiotherapy only. More importantly, inhibition of STAT5 and STAT6 consistently decreased learn more survival after radiation in all cell lines. Although these effects on survival were mostly additive, these data do suggest that inhibition of STAT5 and STAT6 has the potential to improve outcome after radiotherapy in a large proportion of HNSCC patients.