MAP-ing glioma invasion: Mitogen-activated protein kinase kinase 3 and p38 drive glioma invasion and progression and predict patient survival

Abstract

Although astrocytic brain tumors do not metastasize systemically, during tumorigenesis glioma cells adopt an invasive phenotype that is poorly targeted by conventional therapies; hence, glioma patients die of recurrence from the locally invasive tumor population. Our work is aimed at identifying and validating novel therapeutic targets and biomarkers in invasive human gliomas. Transcriptomes of invasive glioma cells relative to stationary cognates were produced from a three-dimensional spheroid in vitro invasion assay by laser capture microdissection and whole human genome expression microarrays. Qualitative differential expression of candidate invasion genes was confirmed by quantitative reverse transcription-PCR, clinically by immunohistochemistry on tissue microarray, by immunoblotting on surgical specimens, and on two independent gene expression data sets of glial tumors. Cell-based assays and ex vivo brain slice invasion studies were used for functional validation. We identify mitogen-activated protein kinase (MAPK) kinase 3 (MKK3) as a key activator of p38 MAPK in glioma; MKK3 activation is strongly correlated with p38 activation in vitro and in vivo. We further report that these members of the MAPK family are strong promoters of tumor invasion, progression, and poor patient survival. Inhibition of either candidate leads to significantly reduced glioma invasiveness in vitro. Consistent with the concept of synthetic lethality, we show that inhibition of invasion by interference with these genes greatly sensitizes arrested glioma cells to cytotoxic therapies. Our findings therefore argue that interference with MKK3 signaling through a novel treatment combination of p38 inhibitor plus temozolomide heightens the vulnerability of glioma to chemotherapy. [Mol Cancer Ther 2007;6(4):1212 -22]

Proline isomerisation as a novel regulatory mechanism for p38MAPK activation and functions

“…41,42 Although the direct correlation between expression of cyclophilins and phosphorylation of p38MAPK has not been established, increased levels of phosphorylated p38MAPK have been described in various cancers. 8,9,[12][13][14]35,43 In this study, we found that cyclophilinmediated isomerisation could be a critical step in the activation of p38MAPK, which could explain the correlative evidence in the literature concerning the overexpression of cyclophilins and an increase in p38MAPK phosphorylation. This in turn could suggest that different cyclophilins and in particular CypA can function as a molecular switch to modulate p38MAPK signalling to adjust to environmental changes, thus modulating cancer cell survival.…”

“…[11][12][13] In addition, inhibition of p38MAPK activity enhances apoptosis and cell sensitivity during administration of chemotherapy drugs. [14][15][16][17] The key regulatory sequence within p38MAPK is Thr180-Gly181-Tyr182, in which Thr and Tyr residues are phosphorylated to increase p38MAPK activity by allowing easier access to its active site. 18 Whether there are additional mechanisms to control p38MAPK activity and functions however remains largely unknown.…”

BRCA1-IRIS overexpression abrogates UV-induced p38MAPK/p53 and promotes proliferation of damaged cells

“…It is possible that in BRCA1-IRIS-silenced cells the induction of replication arrest (ElShamy and Livingston, 2004) activates p38MAPK, as was shown recently (Im and Lee, 2008;Rodrı´guez-Bravo et al, 2007). However, in undamaged BRCA1-IRIS overexpressing cells, perhaps p38MAPK is activated to induce cell survival and/or motility (Suarez-Cuervo et al, 2004;Demuth et al, 2007;Hsieh et al, 2007;Junttila et al, 2007). Alternatively, as p-p38MAPK phosphorylates HuR in the nucleus and enhances its cytoplasmic translocation (Gorospe, 2003;Tran et al, 2003;Lafarga et al, 2009), it is possible that in undamaged cells, this is how BRCA1-IRIS induces HuR cytoplasmic translocation (this study).…”

Mutant p53-induced Up-regulation of Mitogen-activated Protein Kinase Kinase 3 Contributes to Gain of Function

“…MAP2K3 is a specific upstream activator of the p38 MAPK protein (28). Recent studies found that MAP2K3 up-regulation was involved in invasion and progression of gliomas and breast tumors (29). Our recent quantitative PCR validation of microarray data, from cells expressing endogenous mutp53 (HT29 and SKBR3) and xenograft tumors, indicated that MAP2K3 (also known as MKK3) is a mutp53 target gene (11).…”