Secretory autophagy promotes Rab37-mediated exocytosis of tissue inhibitor of metalloproteinase 1

Journal of Biomedical Science

Research

Yeh-Shiu Chu¹  Sheng-Hui Lan²  Hsi-Yu Liu³  Jia-Wen Chen³  Hsiao-Sheng Liu⁴  Kai-Ying Lan⁵  Shan-Ying Wu⁶  Yi-Ching Wang⁷  Chi-Ying Huang⁸ 

[1] Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan;Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, No. 155, Sec. 2, Linong Street, 112, Taipei, Taiwan (R.O.C.);Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan;Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan;Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan;M.Sc. Program in Tropical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;Center for Cancer Research, College of Medicine, Kaohsiung Medical University, No. 100, Shin-Chuan 1st Road, Sanmin Dist., 80708, Kaohsiung City, Taiwan;Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan;Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan;Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan;Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan;Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan;Institute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan;

关键词: Autophagy;    Rab37;    TIMP1;    Lung cancer;    Lung-to-lung metastasis model;   

DOI  :  10.1186/s12929-022-00886-z

 received in 2022-08-04, accepted in 2022-11-20,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundRab37-mediated exocytosis of tissue inhibitor of metalloproteinase 1 (TIMP1), an inflammatory cytokine, under serum-depleted conditions which leads to suppression of lung cancer cell metastasis has been reported. Starvation is also a stimulus of autophagic activity. Herein, we reveal that starvation activates Rab37 and induces autophagy.MethodsWe used an overexpression/knockdown system to determine the relationship between autophagy and Rab37 in vitro and in vivo. The autophagy activity was detected by immunoblotting, transmission electron microscope, autophagosome purification, and immunofluorescence under the confocal microscope. Lung-to-lung metastasis mouse model was used to clarify the role of autophagy and Rab37 in lung cancer. Clinical lung cancer patient specimens and an online big database were analyzed.ResultsInitially, we demonstrated that active-form Rab37 increased LC3-II protein level (the marker of autophagosome) and TIMP1 secretion. Accordingly, silencing of Rab37 gene expression alleviated Rab37 and LC3-II levels as well as TIMP1 secretion, and induction of autophagy could not increase TIMP1 exocytosis under such conditions. Moreover, silencing the Atg5 or Atg7 gene of lung cancer cells harboring active-mutant Rab37 (Q89L) led to decreased autophagy activity and TIMP1 secretion. In the lung-to-lung metastasis mouse model, increased TIMP1 expression accompanied by amiodarone-induced autophagy led to decreased tumor nodules and cancer cell metastasis. These phenomena were reversed by silencing the Atg5 or Atg7 gene. Notably, increasing autophagy activity alone showed no effect on TIMP1 secretion under either Rab37 or Sec22b silencing conditions. We further detected colocalization of LC3 with either Rab37 or TIMP1, identified Rab37 and Sec22b proteins in the purified autophagosomes of the lung cancer cells harboring the active-form Rab37 gene, and confirmed that these proteins are involved in the secretion of TIMP1. We reveal that autophagic activity was significantly lower in the tumors compared to the non-tumor parts and was associated with the overall lung cancer patient survival rate.ConclusionsWe are the first to report that autophagy plays a promoting role in TIMP1 secretion and metastasis in a Rab37-dependent manner in lung cancer cells and the lung-to-lung mouse model.

【 授权许可】

CC BY   
© The Author(s) 2022

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