Related Experiment Videos
Impairment of survival factor function potentiates chemotherapy-induced apoptosis in tumor cells
1Research Institute of Molecular Pathology, Vienna, Austria.
Abstract:
The balance between tumor cell proliferation and apoptosis is a critical determinant of malignant tumor outgrowth. In a transgenic mouse model of beta 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 beta tumor cell (betaTC) apoptosis, indicating that IGF-II acts as a survival factor. Here we report that beta 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 betaTCs 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 betaTCs. Furthermore, normal betaTCs 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.
Insights
Insulin-like growth factor II (IGF-II) promotes beta tumor cell survival. Lack of IGF-II increases tumor cell apoptosis, enhancing chemotherapy effectiveness and suggesting new cancer therapy strategies targeting survival factors.
Area of Science:
- Endocrinology
- Cancer Biology
- Molecular Oncology
Background:
- Tumorigenesis involves a balance between cell proliferation and apoptosis.
- Insulin-like growth factor II (IGF-II) is upregulated during beta cell tumor onset in the Rip1Tag2 mouse model.
- IGF-II acts as a survival factor, as its disruption increases beta tumor cell apoptosis.
Purpose of the Study:
- To investigate the role of IGF-II in beta tumor cell survival and apoptosis.
- To determine if IGF-II deficiency sensitizes beta tumor cells to chemotherapeutic agents.
- To explore novel cancer therapeutic strategies targeting IGF-mediated signaling.
Main Methods:
- Utilized a transgenic mouse model of beta cell tumorigenesis (Rip1Tag2).
- Derived and analyzed beta tumor cell lines from IGF-II-deficient and wild-type Rip1Tag2 mice.
- Assessed apoptosis in response to various stimuli (serum deprivation, staurosporine, chemotherapy) and IGF-I receptor inhibition.
Main Results:
- IGF-II-deficient beta tumor cell lines exhibit higher spontaneous apoptosis rates.
- These cells are more sensitive to apoptotic stimuli and chemotherapeutic agents (daunomycin, etoposide, vincristine).
- Transfection of normal beta tumor cells with a dominant-negative IGF-I receptor mutant sensitizes them to chemotherapy.
Conclusions:
- IGF-II is a critical survival factor for beta tumor cells.
- The absence of IGF-II potentiates the efficacy of chemotherapy against beta tumor cells.
- Interfering with IGF-mediated signaling presents a promising avenue for novel cancer therapies.