title: Signaling pathways involved in the inhibition of epidermal growth factor receptor by erlotinib in hepatocellular cancer.
abstract: OBJECTIVE
  To examine the underlying mechanisms of erlotinib-induced growth inhibition in hepatocellular carcinoma (HCC).
  
  
  METHODS
  Erlotinib-induced alterations in gene expression were evaluated using cDNA array technology; changes in protein expression and/or protein activation due to erlotinib treatment as well as IGF-1-induced EGFR transactivation were investigated using Western blotting.
  
  
  RESULTS
  Erlotinib treatment inhibited the mitogen activated protein (MAP)-kinase pathway and signal transducer of activation and transcription (STAT)-mediated signaling which led to an altered expression of apoptosis and cell cycle regulating genes as demonstrated by cDNA array technology. Overexpression of proapoptotic factors like caspases and gadds associated with a down-regulation of antiapoptotic factors like Bcl-2, Bcl-X(L) or jun D accounted for erlotinib's potency to induce apoptosis. Downregulation of cell cycle regulators promoting the G1/S-transition and overexpression of cyclin-dependent kinase inhibitors and gadds contributed to the induction of a G1/G0-arrest in response to erlotinib. Furthermore, we displayed the transactivation of EGFR-mediated signaling by the IGF-1-receptor and showed erlotinib's inhibitory effects on the receptor-receptor cross talk.
  
  
  CONCLUSIONS
  Our study sheds light on the under-standing of the mechanisms of action of EGFR-TK-inhibition in HCC-cells and thus might facilitate the design of combination therapies that act additively or synergistically. Moreover, our data on the pathways responding to erlotinib treatment could be helpful in predicting the responsiveness of tumors to EGFR-TKIs in the future.
authors.affiliation: Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Medical Clinic I, Gastroenterology/Infectious Diseases/Rheumatology, Berlin, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Huether
authors.forename: Michael
authors.initials: M
authors.lastname: Hopfner
authors.forename: Andreas P
authors.initials: AP
authors.lastname: Sutter
authors.forename: Viola
authors.initials: V
authors.lastname: Baradari
authors.forename: Detlef
authors.initials: D
authors.lastname: Schuppan
authors.forename: Hans
authors.initials: H
authors.lastname: Scherubl
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D045744:Cell Line, Tumor; D018076:DNA, Complementary / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy*; D011061:Poly A; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D018076:DNA, Complementary; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D011061:Poly A; D007334:Insulin-Like Growth Factor I; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases