Growth inhibition by keratinocyte growth factor receptor of human salivary adenocarcinoma cells through induction of differentiation and apoptosis

doi:10.1073/pnas.191377098

Growth inhibition by keratinocyte growth factor receptor of human salivary adenocarcinoma cells through induction of differentiation and apoptosis

^*Department of Molecular Oral Medicine and Maxillofacial Surgery 1, Hiroshima University Faculty of Dentistry, 1-2-3 Kasumi, Minami-Ku, Hiroshima 734-8553, Japan; ^†National Stem Cell Resource, American Type Culture Collection, Manassas, VA 20110-2209; ^‡Central Research Laboratories, ZERIA Pharmaceutical Co., Ageo 360-0111, Japan; and ^§Center for Cancer Biology and Nutrition, Institute of Bioscience and Technology, Texas A & M University System Health Science Center, Houston, TX 77030-3303

Communicated by Gordon H. Sato, Ministry of Fisheries of Eritrea, Baltimore, MD (received for review February 26, 2001)

Abstract

We have reported that normal human salivary gland-derived epithelial cells exclusively express keratinocyte growth factor receptor (KGFR). In the process of malignant transformation of human salivary gland tumors, KGFR gene expression disappeared concomitantly with the de novo expression of the fibroblast growth factor receptor 1 (FGFR1) and FGFR4 genes. In the present study, we introduced wild-type KGFR cDNA or chimeric KGFR/FGFR1 cDNA, which encoded the extracellular domain of KGFR and the intracellular domain of FGFR1, into the HSY human salivary adenocarcinoma cell line. The KGFR tyrosine kinase suppressed the activity of FGF receptor substrate 2 (FRS2) and inhibited the growth of HSY by inducing differentiation and apoptosis in vitro and in vivo. Our results provided significant insight into the mechanism of KGFR tumor suppression and suggest that KGFR gene therapy might be a viable method of inhibiting human salivary adenocarcinoma growth.

Footnotes

↵ ¶ To whom reprint requests should be addressed. E-mail: tetsuok{at}hiroshima-u.ac.jp.
Abbreviations:

FGF,

fibroblast growth factor;

FGFR,

fibroblast growth factor receptor;

KGF,

keratinocyte growth factor;

KGFR,

keratinocyte growth factor receptor;

FRS2,

FGF receptor substrate 2;

Grb2,

growth factor receptor-bound protein 2;

MAP,

mitogen-activated protein;

SGE cells,

salivary gland-derived epithelial cells;

TUNEL,

terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling