Investigating the duality of Inpp4b function in the cellular transformation of mouse fibroblasts
Emily Marie Mangialardi1, Keyue Chen1, Brittany Salmon1
1Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
Abstract:
Inositol Polyphosphate 4-Phosphatase, Type II (INPP4B) is a tumour suppressor in breast, ovarian, prostate, thyroid and other cancers, attributed to its ability to reduce oncogenic Akt-signaling. However, emerging studies show that INPP4B also has tumour-promoting properties in cancers including acute myeloid leukemia, colon cancer, melanoma and breast cancer. Together these findings suggest that INPP4B may be a context dependent cancer gene. Whether INPP4B functions solely in a tumour suppressing or tumour promoting manner, or both in non-transformed cells is currently not clear. In this study, consequences of deficiency and overexpression of INPP4B on cellular transformation was investigated using a mouse embryonic fibroblast (MEF) model of cellular transformation. We observed that neither deficiency nor overexpression of INPP4B was sufficient to induce neoplastic transformation, alone or in combination with H-Ras or E1A overexpression. However, Inpp4b-deficiency did cooperate with SV40 T-Large-mediated cellular transformation, a finding which was associated with increased phosphorylated-Akt levels. Transformation and phosphorylated-Akt levels were dampened upon overexpression of INPP4B in SV40 T-Large-MEF. Together, our findings support a model where INPP4B function suppresses transformation mediated by SV40 T-Large, but is inconsequential for Ras and E1A mediated transformation.
Insights
Inositol Polyphosphate 4-Phosphatase, Type II (INPP4B) has context-dependent roles in cancer. INPP4B deficiency promotes SV40 T-Large-mediated transformation by increasing Akt signaling, while Ras and E1A transformations are unaffected.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Inositol Polyphosphate 4-Phosphatase, Type II (INPP4B) exhibits dual roles as a tumor suppressor and promoter across various cancers.
- Its context-dependent function suggests a complex role in tumorigenesis, particularly concerning Akt signaling pathways.
- The precise function of INPP4B in non-transformed cells and its specific contributions to different cancer types remain unclear.
Purpose of the Study:
- To investigate the role of INPP4B in cellular transformation using a mouse embryonic fibroblast (MEF) model.
- To determine the consequences of both INPP4B deficiency and overexpression on neoplastic transformation.
- To elucidate the specific pathways and oncogenes with which INPP4B interacts during transformation.
Main Methods:
- Utilized a mouse embryonic fibroblast (MEF) model system.
- Assessed cellular transformation induced by INPP4B deficiency or overexpression, alone and in combination with oncogenes like H-Ras, E1A, and SV40 T-Large.
- Quantified changes in phosphorylated-Akt levels as a key indicator of pathway activation.
Main Results:
- Neither INPP4B deficiency nor overexpression alone was sufficient to induce neoplastic transformation in MEFs.
- INPP4B deficiency cooperated with SV40 T-Large to promote cellular transformation, correlating with elevated phosphorylated-Akt levels.
- Overexpression of INPP4B in SV40 T-Large-transformed MEFs reduced transformation and phosphorylated-Akt levels.
- INPP4B's role was found to be inconsequential in H-Ras and E1A-mediated transformation.
Conclusions:
- INPP4B acts as a suppressor of SV40 T-Large-mediated cellular transformation.
- The tumor-suppressive function of INPP4B is linked to the modulation of Akt signaling.
- INPP4B's influence on transformation is context-dependent, specifically regarding the transforming agent involved.
