Manassantin A inhibits tumour growth under hypoxia through the activation of chaperone-mediated autophagy by modulating Hsp90 activity

Jun Kyu Byun, Sun Hee Lee, Eui Jung Moon, Myo Hyeon Park, Hyeonha Jang, Douglas H. Weitzel, Hyun Hwi Kim, Nikita Basnet, Do Yeon Kwon, Chen Ting Lee, Tesia N. Stephenson, Ji Hak Jeong, Bhargav A. Patel, Sung Jean Park, Jen Tsan Chi, Mark W. Dewhirst, Jiyong Hong, You Mie Lee

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageEnglish
Pages (from-to)1491-1502
Number of pages12
JournalBritish Journal of Cancer
Volume128
Issue number8
DOIs
StatePublished - 12 Apr 2023

Fingerprint

Dive into the research topics of 'Manassantin A inhibits tumour growth under hypoxia through the activation of chaperone-mediated autophagy by modulating Hsp90 activity'. Together they form a unique fingerprint.

Cite this