The extracellular domain of p185(c-neu) induces density-dependent inhibition of cell growth in malignant mesothelioma cells and reduces growth of mesothelioma in vivo.
EGFR is involved in the density-dependent inhibition of cell growth, while coexpression of EGFR with erbB2 can render normal cells transformed. In this study, we have examined the effect of a species of p185 that contains the transmembrane domain and the extracellular domain of p185(c-neu), on growth properties of a human malignant mesothelioma cell line that coexpresses EGFR and erbB2. The ectodomain form of p185(c-neu) enhanced density-dependent inhibition of cell growth and we found that p21 induction appeared to be responsible for this inhibitory effect. Previously, the extracellular domain species was shown to suppress the transforming abilities of EGFR and p185(c-neu/erbB2) in a dominant-negative manner. The ability of this subdomain to affect tumor growth is significant, as it reduced in vivo tumor growth. Unexpectedly, we found that the domain did not abrogate all of EGFR functions. We noted that EGFR-induced density-dependent inhibition of cell growth was retained. Tyrosine kinase inhibitors of EGFR did not cause density-dependent inhibition of cell growth of malignant mesothelioma cells. Therefore, simultaneously inhibiting the malignant phenotype and inducing density-dependent inhibition of cell growth in malignant mesothelioma cells by the extracellular domain of p185(c-neu) may represent an important therapeutic advance.
Yoneda
Tsutomu
T
Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Osaka, Japan.
Kumagai
Toru
T
Nagatomo
Izumi
I
Furukawa
Mitsugi
M
Yamane
Hiroyuki
H
Hoshino
Shigenori
S
Mori
Masahide
M
Takeda
Yoshito
Y
Horai
Takeshi
T
Nishida
Sumiyuki
S
Watanabe
Dai
D
Kijima
Takashi
T
Yoshida
Mitsuhiro
M
Osaki
Tadashi
T
Tachibana
Isao
I
Greene
Mark I
MI
Kawase
Ichiro
I
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000235:genetics; D016193:G1 Phase; D015870:Gene Expression; D018734:Genes, erbB-2; D006801:Humans; D008654:Mesothelioma / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008954:Models, Biological; D009368:Neoplasm Transplantation; D017434:Protein Structure, Tertiary; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014183:Transplantation, Heterologous
D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D011994:Recombinant Proteins