Inhibition of N-linked glycosylation using tunicamycin causes cell death in malignant cells: role of down-regulation of the insulin-like growth factor 1 receptor in induction of apoptosis - PubMed (original) (raw)

. 1997 Feb 1;57(3):543-8.

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Inhibition of N-linked glycosylation using tunicamycin causes cell death in malignant cells: role of down-regulation of the insulin-like growth factor 1 receptor in induction of apoptosis

A Dricu et al. Cancer Res. 1997.

Abstract

Recent studies have shown that inhibition of N-linked glycosylation using tunicamycin (TM) induces cell death in cultured cells (O. Larsson et al., J. Cell Sci., 106: 299-307, 1993; J. Y. Chang and V. Korolev, Exp. Neurol., 137: 201-211, 1996). The mechanisms underlying TM-induced cell death seem, however, to be complex in nature. In SV40-transformed cells, TM triggers within a few minutes mechanisms subsequently leading to apoptosis. These mechanisms, although still not fully understood, involve an elevation of [Ca2+]i (M. Carlberg et al., Carcinogenesis, 17: 2589-2596, 1996). In contrast, in melanoma cells, TM has to be present continuously for 24-48 h to elicit apoptosis. Before the appearance of apoptotic melanoma cells, assayed by gel-electrophoretic detection of oligonucleosomally fragmented DNA, the binding of insulin-like growth factor I (IGF-I) to the cells had become drastically decreased, which in turn was found to be due to down-regulation of IGF-I receptor proteins at the cell surface. Incubation of the cells with an antibody (alpha IR-3) against the IGF-I-binding site of the receptor resulted also in apoptosis, the kinetics of which were almost identical to those following treatment with TM. Furthermore, coincubation of a high concentration of IGF-I (50 ng/ml) with TM totally rescued the melanoma cells from apoptotic cell death during the first 48 h after addition of the drugs. This effect was shown to be abolished fully by alpha IR-3. Taken together, our data suggest strongly that N-linked glycosylation plays an important role in maintenance of viability of melanoma cells through regulating the translocation of IGF-I receptor to the cell surface.

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