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

The balance between tumor cell proliferation and apoptosis is a critical determinant of malignant tumor outgrowth. In a transgenic mouse model of β 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 β tumor cell (βTC) apoptosis, indicating that IGF-II acts as a survival factor. Here we report that β 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 βTCs 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 βTCs. Furthermore, normal βTCs 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.