Expression of a truncated EGF receptor is associated with inhibition of pancreatic cancer cell growth and enhanced sensitivity to cisplatinum.
Human pancreatic cancers over-express the epidermal growth factor receptor (EGF-R) and all 5 known ligands of the EGF family, including EGF, transforming growth factor-alpha (TGF-alpha), amphiregulin, betacellulin and heparin-binding EGF-like growth factor (HB-EGF). The aim of the present study was to confirm the presence of EGF-R-dependent autocrine loops in a human pancreatic cancer cell line and to explore the possibility that interrupting EGF-R activation by introducing a truncated receptor abrogates pancreatic cancer cell growth. The anchorage-independent growth of PANC-1 human pancreatic cancer cells, previously shown to express TGF-alpha, was inhibited by specific anti TGF-alpha antibodies. PANC-1 cells were then either transfected with an expression plasmid encoding a kinase-deficient EGF-R cDNA (HER653) or infected with the same EGF-R cDNA using a retroviral vector. Multiple transfected and infected clones co-expressed the truncated EGF-R and endogenous EGF-R as revealed by Northern blot analysis and immunoblots. In these clones, there was a marked attenuation in EGF- and TGF-alpha-mediated EGF-R tyrosine phosphorylation and c-fos induction. There was also a significant decrease in colony formation in soft agar by comparison with control cells and a significant increase in the effect of the growth-inhibitory effect of the alkylating agent cisplatinum in these clones. Our observations indicate that dominant negative inhibition of EGF-R may have therapeutic potential in pancreatic cancer.
Wagner
M
M
Division of Endocrinology, Diabetes and Metabolism, University of California, Irvine 92697, USA.
Cao
T
T
Lopez
M E
ME
Hope
C
C
van Nostrand
K
K
Kobrin
M S
MS
Fan
H U
HU
Büchler
M W
MW
Korc
M
M
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology*; D066246:ErbB Receptors / Q000032:analysis / Q000096:biosynthesis* / Q000737:chemistry; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016372:RNA, Antisense / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
D000970:Antineoplastic Agents; D016760:Proto-Oncogene Proteins c-fos; D016372:RNA, Antisense; D014443:Tyrosine; D066246:ErbB Receptors; D002945:Cisplatin