p38 MAPK in pancreatic cancer: finding a protective needle in the haystack

Abstract

Activated p38 MAPK alpha (pp38α) is a good prognostic marker in pancreatic ductal adenocarcinoma that could be used to personalize therapy. pp38α suppresses JNK-mediated proliferation, both in vitro and in vivo. These findings support the testing of combination therapies that include JNK targeting and/or suppressing negative regulators of pp38α.

Figure 1

Uncovering phospho-p38 MAPK as a good prognostic marker that suppresses JNK-induced mitogenesis in pancreatic cancer. A. A discovery tissue microarray (TMA) and a validation TMA were used to identify increased phospho-p38 MAPK (pp38) as a good prognostic marker in PDAC. B. Schematic representation of MAPK signaling pathways. Stress pathways, growth factors, and cytokines can activate MAPK signaling. The indicated MAPK kinase kinases (MAP3Ks) activate MAPK kinases (MAP2Ks), which activate MAPKs, as explained in the text. In general MKK4/7 activate JNKs, whereas MKK3/6 activate p38 MAPKs. In addition, MKK4 can activate p38 MAPK alpha (p38α). Activated p38α (pp38α) can in turn inhibit MKK4/7, thereby blocking JNK activation and abrogating its growth-stimulatory actions. In addition, activated p38α can suppress mitogenic signaling through other mechanisms as discussed in the text.