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Crosstalk between PI3K and Ras pathways via protein phosphatase 2A in human ovarian clear cell carcinoma
- Source :
- Cancer Biology & Therapy
- Publication Year :
- 2015
- Publisher :
- Informa UK Limited, 2015.
-
Abstract
- Hypoxia-inducible factor-1 (HIF-1) is one of the most promising pharmacological targets for all types of cancer, including ovarian cancer. Ovarian clear cell carcinoma (OCCC) has poor prognosis because of its insensitivity to chemotherapy. To elucidate the characteristics of this troublesome cancer, we examined HIF-1α expression under normoxia or hypoxia in various ovarian cancer cell lines. HIF-1α was highly expressed under normoxia only in RMG-1, an OCCC cell line. To examine whether HIF-1 is involved in the tumorigenesis of RMG-1 cells, we established HIF-1α-silenced cells, RMG-1HKD. The proliferation rate of RMG-1HKD cells was faster than that of RMG-1 cells. Furthermore, the activity of MEK/ERK in the Ras pathway increased in RMG-1HKD cells, whereas that of mTOR in the PI3K pathway did not change. Activation of the Ras pathway was attributable to the increase in phosphorylated MEK via PP2A inactivation. To confirm the crosstalk between the PI3K and Ras pathways in vivo, RMG-1 or RMG-1HKD cells were transplanted into the skin of nude mice with rapamycin (an inhibitor of mTOR), PD98059 (an inhibitor of MEK), or both. RMG-1HKD cells showed higher sensitivity to PD98059 than that observed in RMD-1 cells, whereas the combination therapy resulted in synergistic inhibition of both cells. These findings suggest that inhibition of HIF-1, a downstream target of mTOR in the PI3K pathway, activates the Ras pathway on account of the increase in MEK phosphorylation via PP2A inactivation, and the crosstalk between the 2 pathways could be applied in the combination therapy for HIF-1-overexpressing cancers such as OCCC.
- Subjects :
- MAPK/ERK pathway
Cancer Research
Biology
medicine.disease_cause
Proto-Oncogene Proteins p21(ras)
Mice
Phosphatidylinositol 3-Kinases
Oxygen Consumption
Cell Line, Tumor
Anti-apoptotic Ras signalling cascade
medicine
Animals
Humans
Protein Phosphatase 2
Phosphorylation
Protein Kinase Inhibitors
PI3K/AKT/mTOR pathway
Cell Proliferation
Ovarian Neoplasms
Sirolimus
Pharmacology
MEK inhibitor
TOR Serine-Threonine Kinases
HIF-1
Ras pathway
Protein phosphatase 2
Hypoxia-Inducible Factor 1, alpha Subunit
medicine.disease
Research Papers
PP2A
Cell biology
Gene Expression Regulation, Neoplastic
PI3K pathway
Disease Models, Animal
Crosstalk (biology)
ovarian clear cell carcinoma
Oncology
mTOR
Molecular Medicine
Female
Mitogen-Activated Protein Kinases
Ovarian cancer
Carcinogenesis
Adenocarcinoma, Clear Cell
Protein Binding
Signal Transduction
Subjects
Details
- ISSN :
- 15558576 and 15384047
- Volume :
- 16
- Database :
- OpenAIRE
- Journal :
- Cancer Biology & Therapy
- Accession number :
- edsair.doi.dedup.....b8f8aad78b7053e83c99ff3d2cff8bbf