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Evaluation of Akt and RICTOR Expression Levels in Astrocytomas of All Grades
Arthur William Alvarenga1, Luis Eduardo Machado1, Bruna Roz Rodrigues1
1International Research Center (AWA, LEM, BRR, FCSL, EM, MR, VRM, GNMH).
Abstract:
The mammalian target of rapamycin (mTOR) binds to several protein partners and forms two complexes, termed mTOR complexes 1 and 2 (mTORC1/2), that differ in components, substrates, and regulation. mTORC2 contains the protein Rapamycin-insensitive companion of mTOR (RICTOR); phosphorylates kinases of the AGC family, such as Akt; and controls the cytoskeleton. Even though the regulation of mTORC2 activity remains poorly understood, the hyperactivation of this signaling pathway has been shown to contribute to the oncogenic properties of gliomas in experimental models. In this work, we evaluated expression and phosphorylation of Akt, and expression of RICTOR and Ki-67 in 195 human astrocytomas of different grades (38 cases of grade I, 49 grade II, 15 grade III, and 93 grade IV) and 30 normal brains. Expression and phosphorylation of Akt increased with histological grade and correlated with a worse overall survival in glioblastomas (GBMs). RICTOR was overexpressed in grade I and II astrocytomas and demonstrated a shift to nuclear localization in GBMs. Nuclear RICTOR was associated to increased proliferation in GBMs. Our results point to an increase in total and phosphorylated Akt in high-grade gliomas and to a possible role of RICTOR in proliferations of high-grade GBM cells.
Insights
The mammalian target of rapamycin complex 2 (mTORC2) pathway, involving Akt and RICTOR, is hyperactivated in high-grade gliomas. Increased Akt and nuclear RICTOR correlate with tumor grade and proliferation, suggesting a role in glioma oncogenesis.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Cell Signaling
Background:
- The mammalian target of rapamycin (mTOR) forms two complexes, mTORC1 and mTORC2, with distinct functions.
- mTORC2, containing RICTOR, phosphorylates Akt and influences the cytoskeleton.
- Hyperactivation of mTOR signaling is implicated in glioma development.
Purpose of the Study:
- To investigate the expression and phosphorylation of Akt and RICTOR in human astrocytomas of varying grades.
- To correlate these molecular changes with tumor grade, proliferation (Ki-67), and patient survival.
Main Methods:
- Analysis of Akt (total and phosphorylated) and RICTOR expression and localization in 195 astrocytomas and 30 normal brain tissues.
- Assessment of Ki-67 as a proliferation marker.
- Correlation of molecular findings with histological grade and overall survival.
Main Results:
- Akt expression and phosphorylation increased with astrocytoma grade.
- Akt levels correlated with worse survival in glioblastomas (GBMs).
- RICTOR was overexpressed in low-grade astrocytomas and showed nuclear localization in GBMs, associated with increased proliferation.
Conclusions:
- High-grade gliomas exhibit increased total and phosphorylated Akt.
- RICTOR may play a role in the proliferation of high-grade GBM cells, with nuclear localization being a key indicator.
