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Phenotypic Diversity of -Glutamyltranspeptidase Activity and Protein Secretion in Hepatoma Cell Lines¹

McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, Wisconsin 53706 [W. L. R., V. R. P.], and Department of Biochemistry, Hokkaido University School of Medicine, Sapporo 060, Japan [Y. T.]

Characteristics and patterns of -glutamyltranspeptidase (GGT) expression were studied in four rat and three human hepatoma cell lines. Phenotypic diversity of GGT expression was demonstrated by the following findings. (a) GGT specific activity increased rapidly in three of four rat lines during the first 72 hr after subculture. (b) GGT activity was detected in the fourth rat cell line only from 96 to 120 hr after subculture. (c) In late log or stationary cultures, each of the four rat lines assumed a unique and characteristic level of GGT specific activity. (d) The intracellular GGT distribution pattern was markedly varied in rat and human cell lines. (e) GGT activity was confined to isolated cell clusters in one human line in vitro and one rat line both in vivo and in vitro. And (f) there was poor correlation between GGT specific activity and several liver-associated and hepatoma-associated properties.

In contrast to evidence of diversity in GGT expression, GGT was shown to be a nonsecreted protein in all four rat cell lines.

The constitutive or autogenous nature of the GGT phenotype in rat hepatoma cells was demonstrated by the retention of the GGT-positive and GGT-negative phenotypes of two strains grown in mixed culture; the lack of change in GGT activity when cells were cultured on different substrata, in different media, or in media containing hormones (insulin, dexamethasone, triiodothyronine, or glucagon); and the assumption of nearly constant levels of GGT specific activity in late log or stationary cultures.

The results suggest that GGT activity is expressed in hepatomas as a result of disturbed differentiation and that this expression is not necessarily linked to cell proliferation.

¹ Supported in part by Grants CA-22484 and CA-07175 from the National Cancer Institute, NIH. A preliminary account of this work was presented at the 69th annual meeting of the American Association for Cancer Research (59).

² Recipient of National Cancer Institute Fellowship 5-F32-CA05395-03. To whom requests for reprints should be addressed, at McArdle Laboratory, 450 North Randall Avenue, University of Wisconsin, Madison, Wis. 53706.

³ Supported by the United States-Japan Program for Cancer Research.

⁴ Recipient of Grant CA-17334 from the National Cancer Institute, NIH.

Received 9/22/81. Accepted 1/ 4/82.