Oncogenic Ras modulates @entity1435 MAPK-mediated inflammatory cytokine production in XXXX cells.

@entity32 @entity650 @entity1356 @entity310 @entity470 @entity1441 @entity3820 @entity1916 @entity1435 @entity687 @entity4149 @entity463
UNASSIGNED: Inflammation is an important factor promoting the progression of @entity463 . In the present study we examined the contribution of Ras signaling and @entity310 / @entity1356 cytokines to the development of the @entity463 inflammatory microenvironment. Enhanced activation of Ras through de-regulated activation of receptor @entity4149 kinases, such as @entity470 , @entity3820 and @entity1916 , is a hallmark of the majority of @entity463 . @entity463 microenvironment contains high levels of @entity310 and @entity1356 , which mediate @entity32 through induction of a local network of cytokines and chemokines. While many studies have focused on Ras- and @entity310 / @entity1356 -driven @entity32 in isolation, little is known about the co-operation between these oncogenic and microenvironment-derived stimuli. Using constitutively active HRasG12V that mimics enhanced Ras activation, we demonstrate that elevated Ras activity in @entity463 cells leads to up-regulation of @entity650 and @entity687 . Furthermore, Ras synergizes with the microenvironment-derived @entity310 and @entity1356 resulting in amplified @entity650 / @entity687 secretion. @entity687 secretion induced by Ras and @entity310 / @entity1356 is attenuated by inhibitors targeting Erk, JNK and @entity1435 MAPK pathways. @entity650 secretion significantly decreased upon inhibition of JNK and @entity1435 MAPK pathways. Interestingly, although constitutively active HRasG12V does not increase basal or @entity310 / @entity1356 stimulated @entity1435 MAPK activity, HRasG12V increased the efficacy of the @entity1435 MAPK inhibitor @entity1441 to inhibit @entity1356 -induced @entity650 secretion. In summary, oncogenic Ras co-operates with the microenvironment-derived @entity310 / @entity1356 to sustain inflammatory microenvironment, which was effectively attenuated via inhibition of @entity1435 MAPK signaling.
