Mechanistic role of p38 MAPK in gastric cancer dissemination in a rodent model peritoneal metastasis.

ABSTRACT

Peritoneal dissemination is a highly frequent complication of poorly differentiated gastric cancers for which no effective therapies are available. Constitutive activation of mitogen-activated protein kinases (MAPKs) signaling cascades is recognized as a causative factor in the malignant transformation of several carcinoma cell types. In the present study we provide evidence that p38 MAPK inhibition protects against gastric cancer cells dissemination in a mouse model of peritoneal carcinomatosis. Administering mice with ML3403 and SB203580, potent and selective p38 MAPK inhibitors, attenuate the formation of neoplastic foci induced by intraperitoneal inoculation of gastric cancer cells. By gene array analysis we found that such a protective effect correlates with a robust downregulation in the expression of CXC chemokine receptor-4, Fms-related tyrosine kinase 4 (FLT4), the non-receptor spleen tyrosine kinase (SYK) and the collagen α2(IV) (COL4A2) in neoplasic foci. Inhibition of p38 MAPK in vivo increased the sensitivity of tumor cells to cisplatin and associated with a robust downregulation in the expression of the multidrug resistance (MDR)-1, a well defined marker of resistance to chemotherapy. In summary, p38 MAPK inhibition by a small molecule is beneficial in preventing the peritoneal dissemination of poorly differentiated gastric cancer cells by acting at multiple check-points in the process of attachment and diffusion of tumor cells in the peritoneum.