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Impairment of Survival Factor Function Potentiates Chemotherapy-induced Apoptosis in Tumor Cells¹

Research Institute of Molecular Pathology, A-1030 Vienna, Austria

The balance between tumor cell proliferation and apoptosis is a critical determinant of malignant tumor outgrowth. In a transgenic mouse model of ß cell tumorigenesis (Rip1Tag2), insulin-like growth factor II (IGF-II) is up-regulated during the onset of tumor cell proliferation. Disruption of IGF-II expression in these transgenic mice causes a dramatic increase of ß tumor cell (ßTC) apoptosis, indicating that IGF-II acts as a survival factor. Here we report that ß tumor cell lines derived from IGF-II-deficient Rip1Tag2 mice show a higher incidence of apoptosis than their wild-type counterparts. In particular, IGF-II-deficient ßTCs are more sensitive to apoptotic stimuli, such as serum deprivation and staurosporine, and to chemotherapeutic agents, such as daunomycin, etoposide, or vincristine. Thus, the lack of the survival factor IGF-II potentiates chemotherapeutic treatment of ßTCs. Furthermore, normal ßTCs can be sensitized to chemotherapy when transfected with a dominant-negative mutant of the IGF-I receptor. These results demonstrate a pivotal role for IGF-mediated signaling in the survival of tumor cells and, thus, raise the possibility of novel approaches toward cancer therapy by interfering with survival factor function.

¹ This research was supported in part by the Austrian Industrial Research Promotion Fund.

² To whom requests for reprints should be addressed, at Research Institute of Molecular Pathology, Dr. Bohr-Gasse 7, A-1030 Vienna, Austria. Phone: 43-1-797-30-527; Fax: 43-1-7987 153; E-mail: christofori@nt.imp.univie.ac.at.

Received 9/16/97. Accepted 12/12/97.

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