Abstract
Background
Chaperon-mediated autophagy (CMA) has taken on a new emphasis in cancer biology. However, the roles of CMA in hypoxic tumours are poorly understood. We investigated the anti-tumour effects of the natural product ManA through the activation of CMA in tumour progression under hypoxia.
Methods
The effect of ManA on CMA activation was assessed in mouse xenograft models and cells. The gene expressions of HIF-1α, HSP90AA1, and transcription factor EB (TFEB) were analysed using The Cancer Genome Atlas (TCGA) datasets to assess the clinical relevance of CMA.
Results
ManA activates photoswitchable CMA reporter activity and inhibits Hsp90 chaperone function by disrupting the Hsp90/F1F0-ATP synthase complex. Hsp90 inhibition enhances the interaction between CMA substrates and LAMP-2A and TFEB nuclear localisation, suggesting CMA activation by ManA. ManA-activated CMA retards tumour growth and displays cooperative anti-tumour activity with anti-PD-1 antibody. TCGA datasets show that a combined expression of HSP90AA1High/HIF1AHigh or TFEBLow/HIF1AHigh is strongly correlated with poor prognosis in patients with lung cancer.
Conclusions
ManA-induced CMA activation by modulating Hsp90 under hypoxia induces HIF-1α degradation and reduces tumour growth. Thus, inducing CMA activity by targeting Hsp90 may be a promising therapeutic strategy against hypoxic tumours.
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Data availability
All data except for microarray data generated during this study are included in the article or uploaded as Supplementary Information. The accession number for the microarray data reported in this study is GEO: GSE110768.
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Acknowledgements
We thank Dr. Haystead (Duke University) for HS-10, Dr. Masaaki Komatsu (Tokyo Metropolitan Institute of Medical Science) for ATG7 wild-type and KO HeLa cells, Dr. Ballabio (Baylor College of Medicine) for TFEB-3 x Flag expression vector, Dr. Blagg (University of Notre Dame) for cruentaren A, and Dr. Neckers (National Cancer Institute) for pcDNA3-FLAG-tagged wild-type hHsp90a vectors used in this work. We thank Dr. Fitzgerald (Duke University) and Dr. Mook Jr. (Duke University) for the helpful discussions.
Funding
This work was supported by the National Research Foundation of Korea (NRF-2020R1A5A2017323 to YML) and the American Cancer Society (122057-RSG-12-045-01-CDD to JH).
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J-KB, J-HJ, SHL, M-HP, HJ and NB conducted biochemical, cellular, and in vivo experiments and collected data. D-YK and TNS synthesised manassantin A used in this study. SJP and H-HK conducted biophysical measurements. BAP synthesised cruentaren A used in this study. EJM and J-TC conducted gene expression profiling. DHW and C-TL conducted HS-10 resin experiments. EJM conducted the analysis of patient survival data. YML, JH, MWD, J-TC and SJP analysed and discussed the data. YML and JH conceived the project, designed the overall experimental strategy, wrote the manuscript with input from all the authors, and held overall responsibility for the study.
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Byun, JK., Lee, S.H., Moon, E.J. et al. Manassantin A inhibits tumour growth under hypoxia through the activation of chaperone-mediated autophagy by modulating Hsp90 activity. Br J Cancer 128, 1491–1502 (2023). https://doi.org/10.1038/s41416-023-02148-7
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DOI: https://doi.org/10.1038/s41416-023-02148-7
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