Oncogenic Ras modulates p38 MAPK-mediated inflammatory cytokine production in glioblastoma cells

Abstract

Inflammation is an important factor promoting the progression of glioblastoma. In the present study we examined the contribution of Ras signaling and TNFa/IL-1b cytokines to the development of the glioblastoma inflammatory microenvironment. Enhanced activation of Ras through de-regulated activation of receptor tyrosine kinases, such as EGFR, PDGFR and cMet, is a hallmark of the majority of glioblastomas. Glioblastoma microenvironment contains high levels of TNFa and IL-1b, which mediate inflammation through induction of a local network of cytokines and chemokines. While many studies have focused on Ras-and TNFa/IL-1b-driven inflammation 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 glioblastoma cells leads to up-regulation of IL-6 and IL-8. Furthermore, Ras synergizes with the microenvironment-derived TNFa and IL-1b resulting in amplified IL-6/IL-8 secretion. IL-8 secretion induced by Ras and TNFa/IL-1b is attenuated by inhibitors targeting Erk, JNK and p38 MAPK pathways. IL-6 secretion significantly decreased upon inhibition of JNK and p38 MAPK pathways. Interestingly, although constitutively active HRasG12V does not increase basal or TNFa/IL-1b stimulated p38 MAPK activity, HRasG12V increased the efficacy of the p38 MAPK inhibitor SB203580 to inhibit IL-1b-induced IL-6 secretion. In summary, oncogenic Ras co-operates with the microenvironment-derived TNFa/IL-1b to sustain inflammatory microenvironment, which was effectively attenuated via inhibition of p38 MAPK signaling.

Brain Tumor Microenvironment and Host State: Implications for Immunotherapy

“…Active STAT-3 promotes the recruitment of monocytes via CXCL1, CXCL2 expression, and the induction of a suppressive TME by inducing macrophages to the protumor phenotype (58). In addition to the induction of IL6 Ras-MAPK signaling process includes the activation of p38 MAP kinase (59), which plays a critical role in the induction of TGFb mRNA (60). TGFb is a central pleiotropic cytokine in shaping the immunosuppressive TME, inducing the protumor TAM phenotype, impairing dendritic cell (DC) migration and cytokine sections, inhibiting T-cell responses, and limits the infiltration of leukocytes into the tumor (61).…”

EP4 knockdown alleviates glomerulosclerosis through Smad and MAPK pathways in mesangial cells

“…Smad3 is well known as a key regulator of fibrosis in many organ systems, and this is supported by the findings that mice lacking Smad3 are protected against fibrosis in multiple disease models (32)(33)(34). MAPK signaling is able to regulate fibrosis either independently or through cross-talk with Smad pathways (36)(37)(38). It has been reported that both TGF-β1/Smad and ERK/MAPK signaling act as pro-fibrotic pathways accelerated by blood glucose fluctuation (43)(44)(45).…”

“…TGF-β1, a fibrotic stimulus, is able to activate Smad proteins (Smad2 or Smad3) directly to cause renal fibrosis (31)(32)(33)(34). Mitogen-activated protein kinase (MAPK) pathways, which comprise extracellular signal-regulated kinase (ERK), c-JUN N-terminal kinase (JNK) and p38 signaling, have been reported to play a role in inflammatory regulation (35,36), and also contribute to the amplification of transmitted signals to promote cellular processes, including proliferation and differentiation, either in the cytoplasm or nucleus (37,38). Thus, the current study aimed to investigate two areas: Firstly, whether there is a cross-talk effect between Smad3 and MAPKs in glomerulosclerosis; and secondly, whether the phosphorylation of MAPKs may be mediated by EP4 receptors.…”

MK2 Inhibition Induces p53-Dependent Senescence in Glioblastoma Cells

“…We have shown that active MK2 is expressed in clinical glioblastoma specimens and that p38 -MK2 regulates inflammation in the presence of the EGFRvIII and HRasG12V mutants [10,11]. In glioma xenografts, anti-tumour activity of p38 MAPK inhibitor LY2228820 was linked to the reduction of inflammatory tumour microenvironment [12].…”

“…Although a number of different mechanisms by which MK2 promotes tumor growth and therapy resistance have been reported, there are limited data on MK2 signaling in gliomas [10][11][12][13][14]. Gliomas are classified in a range from pilocytic astrocytoma (Grade I), to diffusely infiltrating lower-grade gliomas (Grades II-III) and to high-grade glioblastoma (Grade IV) [15].…”