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Updated: Feb 20, 2026
Translational Orthotopic Models of Glioblastoma Multiforme
Published on: February 17, 2023
mTORC2/AKT/HSF1/HuR constitute a feed-forward loop regulating Rictor expression and tumor growth in glioblastoma
B Holmes1,2, A Benavides-Serrato1,2, R S Freeman2
1Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Abstract:
Overexpression of Rictor has been demonstrated to result in increased mechanistic target of rapamycin C2 (mTORC2) nucleation and activity leading to tumor growth and increased invasive characteristics in glioblastoma multiforme (GBM). However, the mechanisms regulating Rictor expression in these tumors is not clearly understood. In this report, we demonstrate that Rictor is regulated at the level of mRNA translation via heat-shock transcription factor 1 (HSF1)-induced HuR activity. HuR is shown to directly bind the 3' untranslated region of the Rictor transcript and enhance translational efficiency. Moreover, we demonstrate that mTORC2/AKT signaling activates HSF1 resulting in a feed-forward cascade in which continued mTORC2 activity is able to drive Rictor expression. RNAi-mediated blockade of AKT, HSF1 or HuR is sufficient to downregulate Rictor and inhibit GBM growth and invasive characteristics in vitro and suppress xenograft growth in mice. Modulation of AKT or HSF1 activity via the ectopic expression of mutant alleles support the ability of AKT to activate HSF1 and demonstrate continued HSF1/HuR/Rictor signaling in the context of AKT knockdown. We further show that constitutive overexpression of HuR is able to maintain Rictor expression under conditions of AKT or HSF1 loss. The expression of these components is also examined in patient GBM samples and correlative associations between the relative expression of these factors support the presence of these signaling relationships in GBM. These data support a role for a feed-forward loop mechanism by which mTORC2 activity stimulates Rictor translational efficiency via an AKT/HSF1/HuR signaling cascade resulting in enhanced mTORC2 activity in these tumors.
Insights
Mechanistic target of rapamycin C2 (mTORC2) signaling drives glioblastoma growth by activating heat-shock transcription factor 1 (HSF1) and HuR, which increases Rictor translation and promotes tumor progression.
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.
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