Manassantin A inhibits tumour growth under hypoxia through the activation of chaperone-mediated autophagy by modulating Hsp90 activity.
Journal Article (Journal Article)
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.
- Byun, J-K; Lee, SH; Moon, EJ; Park, M-H; Jang, H; Weitzel, DH; Kim, H-H; Basnet, N; Kwon, D-Y; Lee, C-T; Stephenson, TN; Jeong, J-H; Patel, BA; Park, SJ; Chi, J-T; Dewhirst, MW; Hong, J; Lee, YM
- April 2023
Volume / Issue
- 128 / 8
Start / End Page
- 1491 - 1502
Pubmed Central ID
Electronic International Standard Serial Number (EISSN)
Digital Object Identifier (DOI)