mTORC2/AKT/HSF1/HuR constitute a feed-forward loop regulating Rictor expression and tumor growth in glioblastoma

Area of Science:

• Oncology
• Molecular Biology
• Cell Signaling

Background:

• Rictor overexpression enhances mechanistic target of rapamycin C2 (mTORC2) activity, promoting glioblastoma multiforme (GBM) growth and invasiveness.
• The precise mechanisms governing Rictor expression in GBM remain incompletely understood.

Purpose of the Study:

• To elucidate the regulatory mechanisms controlling Rictor expression in GBM.
• To investigate the role of heat-shock transcription factor 1 (HSF1) and HuR in Rictor regulation.
• To identify potential therapeutic targets within the mTORC2/AKT/HSF1/HuR/Rictor signaling pathway.

Main Methods:

• Investigated Rictor mRNA translation regulation using RNA interference (RNAi) and mutant allele expression.
• Assessed the binding of HuR to the Rictor 3' untranslated region.
• Analyzed the activation of HSF1 by mTORC2/AKT signaling.
• Examined the expression of key signaling components in patient-derived GBM samples.

Main Results:

• HSF1-induced HuR activity directly binds Rictor mRNA's 3' UTR, enhancing its translational efficiency.
• mTORC2/AKT signaling activates HSF1, creating a feed-forward loop that sustains Rictor expression and mTORC2 activity.
• RNAi-mediated inhibition of AKT, HSF1, or HuR significantly downregulates Rictor, inhibiting GBM growth in vitro and in mouse xenografts.
• Constitutive HuR overexpression maintained Rictor expression despite AKT or HSF1 loss.
• Expression analysis of GBM patient samples revealed correlative associations supporting the proposed signaling cascade.

Conclusions:

• A feed-forward loop involving AKT/HSF1/HuR signaling enhances Rictor translation and mTORC2 activity in GBM.
• Targeting the AKT/HSF1/HuR axis represents a potential therapeutic strategy for GBM.
• Understanding Rictor translational regulation provides insights into GBM pathogenesis and progression.