2. Academic Validation
  3. Aloperine Suppresses Cancer Progression by Interacting with VPS4A to Inhibit Autophagosome-lysosome Fusion in NSCLC

Aloperine Suppresses Cancer Progression by Interacting with VPS4A to Inhibit Autophagosome-lysosome Fusion in NSCLC

  • Adv Sci (Weinh). 2024 Aug;11(31):e2308307. doi: 10.1002/advs.202308307.
Weina Guo 1 2,  Haifeng Zhou 1,  Jingbo Wang 1,  Junjie Lu 3,  Yalan Dong 1,  Zhenyu Kang 1,  Xiaoyuan Qiu 1,  Xiaohu Ouyang 1,  Qianyun Chen 1,  Junyi Li 1,  Xiang Cheng 4,  Keye Du 5,  Mingyue Li 6,  Zhihao Lin 7,  Min Jin 8,  Lei Zhang 9,  Alexey Sarapultsev 10,  Kuangyu Shi 11,  Fangfei Li 12,  Ge Zhang 13,  Kongming Wu 14,  Yueguang Rong 15,  Vigo Heissmeyer 16,  Yue Liu 17,  Yunlun Li 9 18,  Kun Huang 19,  Shanshan Luo 20,  Desheng Hu 1 21
Affiliations

Affiliations

  • 1 Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China.
  • 2 Department of Laboratory Medicine, Wuhan Children's Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China.
  • 3 Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, 441000, China.
  • 4 Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  • 5 Department of Neurosurgery, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China.
  • 6 Department of Gastroenterology, Zhongda Hospital, Southeast University, Nanjing, 210000, China.
  • 7 Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, 361000, China.
  • 8 Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China.
  • 9 Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, China.
  • 10 School of Medical Biology, South Ural State University, Chelyabinsk, 454087, Russia.
  • 11 Department of Nuclear Medicine, University of Bern, Bern, 3007, Switzerland.
  • 12 Shum Yiu Foon Sum Bik Chuen Memorial Centre for Cancer and Inflammation Research School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, 999077, China.
  • 13 Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, 999077, China.
  • 14 Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China.
  • 15 School of Basic Medicine of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China.
  • 16 Institute for Immunology Biomedical Center, Ludwig-Maximilians-Universität München, 82152, Planegg-Martinsried, Germany.
  • 17 Cardiovascular Disease Center, Xiyuan hospital of China academy of Chinese medical Sciences, Beijing, 100102, China.
  • 18 Innovation Research Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China.
  • 19 School of Pharmacy of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 20 Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China.
  • 21 Hubei Key Laboratory of Biological Targeted Therapy, China-Russia Medical Research Center for Stress Immunology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China.
PMID: 39166458 DOI: 10.1002/advs.202308307
Abstract

Aloperine (ALO), a quinolizidine-type alkaloid isolated from a natural Chinese herb, has shown promising antitumor effects. Nevertheless, its common mechanism of action and specific target remain elusive. Here, it is demonstrated that ALO inhibits the proliferation and migration of non-small cell lung Cancer cell lines in vitro and the tumor development in several mouse tumor models in vivo. Mechanistically, ALO inhibits the fusion of autophagosomes with lysosomes and the autophagic flux, leading to the accumulation of sequestosome-1 (SQSTM1) and production of Reactive Oxygen Species (ROS), thereby inducing tumor cell Apoptosis and preventing tumor growth. Knockdown of SQSTM1 in cells inhibits ROS production and reverses ALO-induced cell Apoptosis. Furthermore, VPS4A is identified as a direct target of ALO, and the Amino acids F153 and D263 of VPS4A are confirmed as the binding sites for ALO. Knockout of VPS4A in H1299 cells demonstrates a similar biological effect as ALO treatment. Additionally, ALO enhances the efficacy of the anti-PD-L1/TGF-β bispecific antibody in inhibiting LLC-derived subcutaneous tumor models. Thus, ALO is first identified as a novel late-stage Autophagy inhibitor that triggers tumor cell death by targeting VPS4A.

Keywords

VPS4A; apoptosis; autophagy inhibition; non‐small cell lung cancer; sequestosome‐1.

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