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Cellular and Molecular Biology

Autophagy mediated lipid catabolism facilitates glioma progression to overcome bioenergetic crisis

British Journal of Cancer volume 124, pages 1711–1723 (2021)Cite this article

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Abstract

Background

Activation of mTORC1 plays a significant role in cancer development and progression. However, the metabolic mechanisms to sustain mTORC1 activation of cancer cells within stressed environments are still under-appreciated. We recently revealed high autophagy activity in tumour cells with mTORC1 hyper-activation. Nevertheless, the functions and mechanisms of autophagy in regulating mTORC1 in glioma are not studied.

Methods

Using glioma patient database and human glioma cells, we assessed the mechanisms and function of selective autophagy to sustain mTORC1 hyper-activation in glioma.

Results

We revealed a strong association of altered mRNA levels in mTORC1 upstream and downstream genes with prognosis of glioma patients. Our results indicated that autophagy-mediated lipid catabolism was essential to sustain mTORC1 activity in glioma cells under energy stresses. We found that autophagy inhibitors or fatty acid oxidation (FAO) inhibitors in combination with 2-Deoxy-D-glucose (2DG) decreased energy production and survival of glioma cells in vitro. Consistently, inhibition of autophagy or FAO inhibitors with 2DG effectively suppressed the progression of xenografted glioma with hyper-activated mTORC1.

Conclusions

This study established an autophagy/lipid degradation/FAO/ATP generation pathway, which might be used in brain cancer cells under energy stresses to maintain high mTORC1 signalling for tumour progression.

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Fig. 1: Analysis of mTORC1 upstream regulators and downstream effectors in glioma patients.
Fig. 2: Maintenance of mTORC1 hyper-activity in GBM cells upon energy stresses through autophagy-mediated lipid degradation.
Fig. 3: Maintenance of mTORC1 hyper-activity in GBM cells upon energy stresses through autophagy-mediated fatty acid oxidation.
Fig. 4: Therapeutic target of autophagy-mediated lipid catabolism in glioblastoma cells.
Fig. 5: Targeting autophagy and glycolysis in a subcutaneously transplanted GBM model.
Fig. 6: Targeting autophagy-mediated fatty acid β-oxidation in an intracranial transplanted GBM model.

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Acknowledgements

We thank Dr. Xin Tang and Mr. Harsh Patel in Dr. Wang’s lab and other people from Dr. Guan’s lab for careful reading of the manuscript and helpful suggestions. We thank Glenn Doerman for his help in the preparation of figures. We thank the support from Brain Tumor Center of University of Cincinnati College of Medicine.

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  1. These authors contributed equally: Chenran Wang, Michael A. Haas

Authors and Affiliations

  1. Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Chenran Wang, Michael A. Haas, Syn Kok Yeo, Ritama Paul, Fuchun Yang, David R. Plas & Jun-Lin Guan

  2. Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Subrahmanya Vallabhapurapu & Xiaoyang Qi

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Contributions

C.W.: developed idea, designed and executed experiments, analysed data and wrote manuscript; M.H.: assisted in the mice transplantation and edited the manuscript; S.Y.: contributed in the development of molecular mechanism, the manuscript review and correction; R.P.: assisted in experiments and edited the manuscript; F.Y.: assisted in experiments and edited the manuscript; S.V.: assisted in the mice transplantation and edited the manuscript; X.Q.: designed experiments, analysed data and edited the manuscript; D.P.: contributed in the development of molecular mechanism, analysed data and edited the manuscript; J.-L.G.: developed idea, analysed data and edited the manuscript.

Corresponding author

Correspondence to Chenran Wang.

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Ethics approval and consent to participate

Mice were housed and handled according to local, state and federal regulations. All animal studies were carried out according to the protocols approved by the Institutional Animal Care and Use Committee at University of Cincinnati (Cincinnati, OH, USA). Human GBM cell lines were gifts from Dr. David R. Plas (University of Cincinnati College of Medicine) as described in the Methods section.

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All original data and materials generated during the current study are available from the corresponding author upon reasonable request.

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The authors declare no competing interests.

Funding information

This study was supported by NIH grants (NS103981-01) to C.R.W. and (NS094144-02, CA211066) to J.L.G.

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Wang, C., Haas, M.A., Yeo, S.K. et al. Autophagy mediated lipid catabolism facilitates glioma progression to overcome bioenergetic crisis. Br J Cancer 124, 1711–1723 (2021). https://doi.org/10.1038/s41416-021-01294-0

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