ABSTRACT
The PI3K/PDK1/Akt signaling axis is centrally involved in cellular homeostasis and controls cell growth and proliferation. Due to its key function as regulator of cell survival and metabolism, the dysregulation of this pathway is manifested in several human pathologies including cancers and immunological diseases. Thus, current therapeutic strategies target the components of this signaling cascade. In recent years, numerous feedback loops have been identified that attenuate PI3K/PDK1/Akt-dependent signaling. Here, we report the identification of an additional level of feedback regulation that depends on the negative transcriptional control of phosphatidylinositol 3-kinase (PI3K) class IA subunits. Genetic deletion of 3-phosphoinositide-dependent protein kinase 1 (PDK1) or the pharmacological inhibition of its downstream effectors, that is, Akt and mammalian target of rapamycin (mTOR), relieves this suppression and leads to the upregulation of PI3K subunits, resulting in enhanced generation of phosphatidylinositol-3,4,5-trisphosphate (PIP3). Apparently, this transcriptional induction is mediated by the concerted action of different transcription factor families, including the transcription factors cAMP-responsive element-binding protein and forkhead box O. Collectively, we propose that PDK1 functions as a cellular sensor that balances basal PIP3 generation at levels sufficient for survival but below a threshold being harmful to the cell. Our study suggests that the efficiency of therapies targeting the aberrantly activated PI3K/PDK1/Akt pathway might be increased by the parallel blockade of feedback circuits.
Subject(s)
Phosphatidylinositol 3-Kinases/metabolism , Phosphatidylinositol Phosphates/metabolism , Protein Serine-Threonine Kinases/metabolism , Animals , Cell Line , Cell Membrane/metabolism , Cell Survival/genetics , Chickens , Feedback, Physiological , Gene Expression Profiling , Gene Expression Regulation , Humans , Jurkat Cells , Phosphatidylinositol 3-Kinases/genetics , Pyruvate Dehydrogenase Acetyl-Transferring Kinase , Signal Transduction/drug effects , Signal Transduction/genetics , Signal Transduction/radiation effects , TOR Serine-Threonine Kinases/antagonists & inhibitorsABSTRACT
AIM: Salivary glands (SG) can become atrophic following radiation exposure. Malignant transformation of SG in a radiation field is another known sequela of patients who have been treated by radiotherapy for a malignant tumor in the head and neck region. The aim of this study was to investigate cytogenetic alterations and to determine the proliferation index (PI) of SG of rats subjected to various total dosages of fractionated X-rays. MATERIALS AND METHODS: We investigated rat SG, subjected to 20, 40, or 60 Gy exposure by X-rays to the left neck and skull base. Non-irradiated rats served as a control group. Tumors originating from the SG were histologically-diagnosed following the descriptions for human SG tumors. The MIB-5 antibody was used to determine the PI. The ploidy was determined by flow and image cytometry (FCM, ICM). RESULTS: We consistently recorded diploid histograms in the FCM in irradiated glands. ICM revealed aneuploid histograms in 6/22 tumors, 3 of them were Auer Type III or IV. The PI showed a dose- and time-dependent course, indicative of variable regeneration properties of the parenchyma. Statistically significant differences were found for the PI within the irradiation groups and comparing irradiated SG and tumors. CONCLUSION: Irradiation of rat SG can cause almost complete loss of function. On the other hand, the PI remained in animals subjected to 40 Gy and investigated 1 year after completion of radiation at a level up to 10-fold higher than in untreated controls. The PI in carcinoma is higher in this species than in irradiated SG. Constantly elevated PI could support the development of cancer in SG.
