Involvement of p38 mitogen-activated protein kinase signaling in transformed growth of a cholangiocarcinoma cell line

Although mitogen-activated protein kinase (MAPK) pathways play a key role i n cell growth, their role in mediating the altered growth phenotype of tran sformed cells remains unclear. The p44/p42 MAPK signaling cascades are acti vated by mitogenic stimulation of human cholangiocytes. In contrast, the p3 8 MAPK pathway is activated by mitogen stimulation of malignant, but not no nmalignant cholangiocytes, Thus, our aims were to determine the role of p38 MAPK signaling in mediating the growth phenotype of transformed cholangioc ytes. KMCH-1 malignant human cholangiocytes required the presence of serum for proliferation, but were able to grow in reduced serum conditions. Inhib ition of p38 MAPK decreased serum-dependent proliferation of KMCH-1 cells, Furthermore, inhibition of p38 MAPK, but not of p44/p42 MAPK, reduced ancho rage-independent growth of KMCH-1 cells. Although both p38 and p44/p42 MAPK are activated in response to mitogens, they have divergent effects on anch orage-independent growth. Inhibition of p38 MAPK, but not of p44/p42 MAPK s ignaling, decreased cell cycle progression and increased expression of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) However, expression of p27 (KIP1) Or p16(INK4A) was not altered by either pathway. Thus, mitogen activ ation of p38 MAPK decreases expression of p21(WAF1/CIP1) and mediates growt h independent of anchorage signals, whereas mitogen activation of p44/p42 M APK mediates an anchorage signal-dependent growth pathway. These data provi de a link between aberrant stress-activated cell signaling and the altered growth phenotype of transformed cells that may be important for the develop ment of therapies to limit transformed cell growth.