Speaker Biography

Guan Chen

Department of Pharmacology and Toxicology,Medical College of Wisconsin,USA

Title: p38 MAPK signaling and pancreatic tumorigenesis

Guan Chen

Ras is the most established oncogene in human cancer, with its mutation (K-Ras) occurring in about 50% human colon cancer and its hyperexpression (H-Ras) in more than 50% of human breast cancer. Ras oncogene activity, however, is determined by downstream effectors and elucidation of this regulation is essential to understand why not all Ras mutations can lead to human malignancies. MAPKs (mitogen-activated protein kinases), including ERK, JNK, and p38, signal downstream of Ras by converting extracellular and Ras signals into specific cellular response through a group of transcription factors. Our previous work established that Ras-induced p38 alpha phosphorylation/activation inhibits the oncogene activity by negative feedback. Results from our recent studies further showed that p38 gamma, a p38 family protein, is induced by Ras and in turn required for Ras transformation in rat intestinal epithelial cells and for Ras-invasive activity in human breast cancer. These results together indicate that signaling integrations among p38 family members determine Ras oncogene activity in a given tissues and p38 proteins regulate Ras activity by isoform-dependent mechanisms. Currently, we are investigating mechanisms by which Ras induces p38 gamma expression and by which p38gamma is required for Ras-induced transformation / invasion.
Nuclear receptors are group of transcription factors that play an important role in reproduction, homeostasis, and cancer development through regulating gene expression in response to their ligand. Our second research interest is to study signal cross-talks between Ras/MAPK pathways and nuclear receptors. Studies from our lab have established a c-Jun/AP-1 dependent trans-activation for stress-induced vitamin D receptor (VDR) expression and an anti-apoptotic activity of VDR by a K-ras-dependent mechanism. Our results further showed that another nuclear receptor ER (estrogen receptor) inhibits stress MAPK-mediated cell death independent of its transcriptional activity by converting pro-apoptotic c-Jun activity into a c-Jun-dependent AP1 transcription. These results together suggest that nuclear receptors may cooperate with Ras/MAPKs to regulate stress-response independent of their transcription activity. We are currently investigating whether regulation of nuclear receptors represents a novel strategy for human cancer treatment.


Pancreatic ductal cancer (Pda) lacks established therapeutic targets and is consequently among the deadliest malignancies with near-universal K-Ras mutations. Here, we report that a Kras effector p38g (MAPK12) is required for pancreatic tumorigenesis through stimulating metabolic reprogramming. Both conditional p38g knockout and pharmacological inhibition decrease pancreatic tumorigenesis and inhibit Pda growth. Mechanistically p38g binds PFKFB3 dependent of mutated Kras and phosphorylates this glycolytic activator at S467, which is required for aerobic glycolysis and Pda growth. Activation of the p38g/p-PFKFB3 pathway in clinic specimens further correlates with decreased patient survival. Thus, p38g MAPK is essential for Pda tumorigenesis by linking K-Ras oncogene activity and metabolic reprogramming and may be targeted for therapeutic intervention