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

• Published in: British journal of cancer Vol. 128; no. 8; pp. 1491 - 1502
• Main Authors: Byun, Jun-Kyu, Lee, Sun Hee, Moon, Eui Jung, Park, Myo-Hyeon, Jang, Hyeonha, Weitzel, Douglas H, Kim, Hyun-Hwi, Basnet, Nikita, Kwon, Do-Yeon, Lee, Chen-Ting, Stephenson, Tesia N, Jeong, Ji-Hak, Patel, Bhargav A, Park, Sung Jean, Chi, Jen-Tsan, Dewhirst, Mark W, Hong, Jiyong, Lee, You Mie
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.04.2023; Nature Publishing Group UK
• Subjects: Animal models; Animals; ATP synthase; Autophagy; Autophagy - genetics; Cancer; Cell culture; Chaperone-Mediated Autophagy; Genomes; HSP90 Heat-Shock Proteins - metabolism; Hsp90 protein; Humans; Hypoxia; Hypoxia-inducible factor 1a; Lung cancer; Lung Neoplasms; Mice; Molecular Chaperones; Natural products; PD-1 protein; Tumors
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-023-02148-7

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. 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. ManA activates photoswitchable CMA reporter activity and inhibits Hsp90 chaperone function by disrupting the Hsp90/F F -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 HSP90AA1 /HIF1A or TFEB /HIF1A is strongly correlated with poor prognosis in patients with lung cancer. 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.