Interferon-alpha and -gamma inhibit the growth and neoplastic potential of v-src-transformed human epithelial cells by reducing Src tyrosine kinase activity.
To investigate whether interferons (IFNs) selectively suppress the growth of solid tumor cells with elevated protein tyrosine kinase (PTK) activity, we evaluated the effect of recombinant IFN-alpha2a and IFN-gamma on the proliferative and neoplastic potentials triggered by p60v-src using v-src-transformed HAG-1 human epithelial cells. When compared with control cells harboring the pSV2neo gene, the monolayer growth of v-src-transformed cell lines was inhibited by both recombinant IFNs, in a dose-dependent manner, whereas growth of ras-transfected cell lines was not affected. Moreover, IFNs markedly reduced the clonogenic growth of v-src-transformed cells in soft-agar rather than monolayer growth, suggesting the preferential activity of IFNs on anchorage-independent growth. Pretreatment of cells with Src or the Src-like PTK inhibitor herbimycin A or radicicol, alleviated dose-dependently the growth-inhibitory activity of IFN-alpha2a against v-src-transformed cells, suggesting that IFNs may share a common inhibitory pathway with Src PTK inhibitors. Accordingly, like herbimycin A, IFNs were found to reduce tyrosine phosphorylation of p60v-src and suppressed in vitro p60v-src kinase activity in v-src-transformed cells. Our data, together with the fact that IFNs inhibit the growth potential driven by Src but not by activated Ras, suggest that inhibition of signal transduction pathway through Src to downstream transduction events may be a primary mechanism of IFN-induced anti-prolifeative and anti-tumoral activity.
Fujishima
H
H
First Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka City, Japan.
Nakano
S
S
Tatsumoto
T
T
Masumoto
N
N
Niho
Y
Y
D000230:Adenocarcinoma / Q000201:enzymology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002461:Cell Line, Transformed / Q000187:drug effects / Q000201:enzymology; D004847:Epithelial Cells / Q000187:drug effects* / Q000201:enzymology; D005706:Gallbladder Neoplasms / Q000201:enzymology; D011905:Genes, ras / Q000235:genetics; D016391:Genes, src / Q000235:genetics*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000187:drug effects* / Q000378:metabolism; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects*
D000970:Antineoplastic Agents; D016898:Interferon-alpha; D014443:Tyrosine; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; D019061:src-Family Kinases