p38gamma MAPK signaling promotes intestinal tumorigenesis

Colorectal cancer (CRC) is the second leading cause of malignant-associated death in the USA with
inflammation as a key driving force for its development, growth, and progression. p38, a member of p38
mitogen-activated protein kinases (p38 MAPK  , and ), is oncogenic, pro-inflammatory, and
overexpressed in clinical CRC but the role of epithelial p38 in CRC tumorigenesis has not been tested. -
catenin, a critical cofactor of Wnt transcription, is aberrantly activated in 90% of CRC. And yet, -catenin is
undruggable and there is thus an urgent need to identify druggable -catenin activators for therapeutic
intervention. Here we propose that p38 MAPK in intestinal epithelial cells (IEC) drives CRC
tumorigenesis by stimulating oncogenic -catenin phosphorylation.
This hypothesis is based on our preliminary studies showing that: 1) inflammation coordinately stimulates
p38 and -catenin phosphorylation in CRC cells; 2) p38 directly phosphorylates -catenin at S605, which
increases -catenin stability, the -catenin-TCF4 interaction, Wnt transcription and CRC growth; 3)
inflammation activates p38, but not p38, in intestinal tissues of mice, and IEC-specific p38 knockout (KO)
reduces pro-inflammatory cytokine expression and attenuates colitis severity; 4) IEC p38 KO inhibits colon
tumorigenesis and p--catenin/S605/Wnt signaling in the azoxymethane (AOM)/dextran sodium sulfate (DSS)
mouse model of colitis-associated cancer (CAC); 5) the p38 pharmacological inhibitor pirfenidone (PFD)
suppresses -catenin/cytokine expression and colon tumorigenesis in wild-type (WT) mice, but not in p38 KO
mice, and further collaborates with the -catenin-TCF4 interaction antagonist LF3 and chemotherapeutic drug
5FU to inhibit CRC growth, and 6) p38 is upregulated in clinical CAC specimens and in intestinal tissues of
Apcmin and interleukin-10 knockout (IL-10-/-) mice. These results together indicate that IEC p38 is required for
tumorigenesis of both CAC and sporadic CRC by stimulating oncogenic -catenin phosphorylation.
Using genetic and pharmacological approaches, we will test this hypothesis by determining (1) if p38-
induced -catenin/S605 phosphorylation stimulates -catenin nuclear translocation, -catenin-TCF4
interaction, Wnt transcription and CRC growth; (2) if IEC-specific p38 KO blocks tumorigenesis in IL-
10-/- and Apcmin mice and if p38 is essential for the -catenin/TCF4/Wnt signaling to promote malignant
progression in CRC pathogenesis; and (3) if the p38 pharmacological inhibitor pirfenidone (PFD)
blocks CRC tumorigenesis and increases the growth-inhibitory activity of LF3 and 5FU by disrupting
the p38/-catenin/TCF4/Wnt pathway. Upon completion, these studies will demonstrate if epithelial p38
promotes CRC tumorigenesis by stimulating oncogenic -catenin/S605 phosphorylation and Wnt transcription.
Demonstrating the effectiveness of PFD in inhibiting Wnt signaling and CRC tumorigenesis by targeting
intestinal epithelial p38 will reveal that drugging p38 has a great potential for colon cancer targeted therapy.

Grant Number: 5R01CA245977-06
NIH Institute/Center: NIH
Principal Investigator: GUAN CHEN