An effect of K-ras gene mutation on epidermal growth factor receptor signal transduction in PANC-1 pancreatic carcinoma cells

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Abstract
The Ras protein is involved in tyrosine kinase signal transduction pathway steps such as EGFR signalling. Most human pancreatic carcinomas harbor a point mutation of K‐ras oncogene and overexpress transforming TGF‐α. We studied how K‐ras gene mutation could influence the EGFR signal transduction mechanism and the autonomous proliferation of pancreatic carcinoma cells, using PANC‐1 human pancreatic carcinoma line and WI‐38 normal human fibroblast cell line as a control. PANC‐1 cells responded to neither EGF nor exogenous TGF‐α, although anti‐TGF‐α MAb suppressed their growth. Expression of TGF‐α mRNA was detected only in PANC‐1 cells, which confirmed EGFR being within an autocrine loop. Ras protein and MAP kinase were constitutively activated in PANC‐1 cells so that the cells did not respond to treatment with staurosporine or herbimycin A, and exhibited slight response to EGF stimulation. PANC‐1 cells harbored K‐ras gene mutation in codon 12. In contrast, EGF stimulation induced an elevation of GTP‐bound ratio to Ras protein and an activation of MAP kinase with accelerated growth in WI‐38 cells. From these findings, we concluded that K‐ras gene mutation possibly plays an important role in the autonomous proliferation of PANC‐1 pancreatic carcinoma cells, and that an autocrine loop represented by TGF‐α and EGFR may further accelerate the growth of PANC‐1 cells.