IMPAIRMENT OF SURVIVAL FACTOR FUNCTION POTENTIATES CHEMOTHERAPY-INDUCED APOPTOSIS IN TUMOR-CELLS

The balance between tumor cell proliferation and apoptosis is a critic al determinant of malignant tumor outgrowth, In a transgenic mouse mod el of beta cell tumorigenesis (Rip1Tag2), insulin like growth factor I I (IGF-LI) is up-regulated during the onset of tumor cell proliferatio n, Disruption of IGF-LI expression in these transgenic mice causes a d ramatic increase of beta tumor cell (beta TC) apoptosis, indicating th at IGF-II acts as a survival factor, Here we report that beta tumor ce ll lines derived from IGP-II-deficient Rip1Tag2 mice show a higher inc idence of apoptosis than their wild-type counterparts, In particular, IGF-II-deficient beta TCs are more sensitive to apoptotic stimuli, suc h as serum deprivation and staurosporine, and to chemotherapeutic agen ts, such as daunomycin, etoposide, or vincristine, Thus, the lack of t he survival factor IGF-II potentiates chemotherapeutic treatment of be ta TCs. Furthermore, normal beta TCs can be sensitized to chemotherapy when transfected with a dominant-negative mutant of the IGF-I recepto r. These results demonstrate a pivotal role for IGF-mediated signaling in the survival of tumor cells and, thus, raise the possibility of no vel approaches toward cancer therapy by interfering with survival fact or function.