Molecular and Cellular Endocrinology 165 (2000) 131 – 137 Tamoxifen-induced cell death in malignant melanoma cells: possible involvement of the insulin-like growth factor-1 (IGF-1) pathway Lena Kanter-Lewensohn a , Leonard Girnita a , Ada Girnita a , Anica Dricu a , Gunilla Olsson a , Louise Leech a , Gunnar Nilsson a , Agneta Hilding b , Johan Wejde a , Kerstin Brismar b , Olle Larsson a, * a Cellular and Molecular Tumor Pathology, CCK R8:04, Department of Oncology /Pathology, Karolinska Hospital, 171 76 Stockholm, Sweden b Department of Molecular Medicine, The Endocrine and Diabetes Unit, Karolinska Hospital, SE-171 76 Stockholm, Sweden Received 8 December 1999; accepted 5 April 2000 Abstract Recent data indicate that the estrogen receptor (ER) blocker tamoxifen (TAM) can induce cell death in malignant melanoma cells. However, as shown in the present study and several other studies melanoma cells usually do not express classical ERs. In the present study we investigated whether the cytotoxic effect of TAM on melanoma cells could depend on interference with the expression or function of the insulin-like growth factor-1 receptor (IGF-1R), a plasma membrane receptor important for cell survival in this tumor cell type. Several melanoma cell lines were included in the analysis. Administration of TAM at a concentration of 15 m or more resulted in cell death of the melanoma cells within 48 h. TAM treatment was correlated to a slight to moderate inhibition of IGF-1 binding to IGF-1R. Since it has been reported that TAM can increase the release of IGF binding proteins (IGFBPs) we then investigated whether this mechanism could underly the decreased IGF-1 binding. However, we could demonstrate that the amount of released IGFBPs were unchanged or decreased in TAM-treated cells. Whereas TAM did not have any strong effect on IGF-1 binding and the expression of IGF-1R at the cell surface, it was was found to efficently block tyrosine phosphorylation of IGF-1R -subunit. Taken together, our data suggest that TAM-induced cytotoxicity of malignant melanoma cells can be due to inactivation of IGF-1R. © 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Malignant melanoma; Tamoxifen; IGF-1 receptor; IGF binding proteins (IGFB) www.elsevier.com/locate/mce 1. Introduction Epidemiological data indicate that female patients with malignant melanoma have better survival com- pared with male patients (Miller et al., 1997). The mechanism of this survival advantage is still unclear. Recent studies have shown that the estrogen receptor (ER) blocker tamoxifen (TAM) inhibits growth of melanoma cells (Piantelli et al., 1995; Gelmann, 1997; Lama et al., 1998). Further, studies on malignant melanoma, although still controversal, have provided us with information that treatment with TAM can sensitize tumors that show clinical resistence to certain cytostatics (Jones and Clemmons, 1995). The mecha- nism of action of this sensitization is still, however, poorly understood (Miller et al., 1997). The current view is that the TAM action is not mediated by its anti-estrogenic properties (McClay and McClay, 1994). In a study by Guvakova and Surmacz (1997), it was shown that the cytostatic effect of TAM on the estro- gen-dependent MCF-7 breast cancer cell line is associ- ated with modulation of the IGF-1R signaling pathway. TAM was shown to down-regulate the IGF- 1-induced tyrosine phosphorylation of the -subunit of IGF-1R and of the insulin receptor substrate-1 (IRS-1, the major substrate of IGF-1R), as well as the phos- phatidylinositol-3 kinase signaling was decreased. We have previously shown that inhibition of the translocation of IGF-1R to the plasma membrane or * Corresponding author. Fax: +46-8-7588397. E-mail address: olle.larsson@onkpat.ki.se (O. Larsson). 0303-7207/00/$ - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved. PII:S0303-7207(00)00253-7