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

✍ Scribed by Masao Watanabe; Aichirou Nobuta; Junji Tanaka; Masahiro Asaka

• Publisher: John Wiley and Sons
• Year: 1996
• Tongue: French
• Weight: 576 KB
• Volume: 67
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/(sici)1097-0215(19960717)67:2<264::aid-ijc18>3.0.co;2-b

✦ Synopsis

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-a. We studied how K-ras gene mutation could influence the EGFR signal transduction mechanism and the autonomous proliferation of pancreatic carcinoma cells, using PANC-I human pancreatic carcinoma line and WI-38 normal human fibroblast cell line as a control. PANC-I cells responded to neither EGF nor exogenous TGF-a, although anti-TGF-a MAb suppressed their growth. Expression of TGF-a mRNA was detected only in PANC-I cells, which confirmed EGFR being within an autocrine loop. Ras protein and MAP kinase were constitutively activated in PANC-I cells so that the cells did not respond to treatment with staurosporine or herbimycin A, and exhibited slight response to EGF stimulation. PANC-I 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-I pancreatic carcinoma cells, and that an autocrine loop represented by TGF-a and EGFR may further accelerate the growth of PANC-I cells.