2. Academic Validation
  3. Proton pump inhibitors enhance macropinocytosis-mediated extracellular vesicle endocytosis by inducing membrane v-ATPase assembly

Proton pump inhibitors enhance macropinocytosis-mediated extracellular vesicle endocytosis by inducing membrane v-ATPase assembly

  • J Extracell Vesicles. 2024 Apr;13(4):e12426. doi: 10.1002/jev2.12426.
Xinliang Lu # 1 2,  Zhengbo Song # 3,  Jiayue Hao # 1 2,  Xianghui Kong # 1 2,  Weiyi Yuan 4,  Yingying Shen 5,  Chengyan Zhang 4,  Jie Yang 6,  Pengfei Yu 7,  Yun Qian 8,  Gensheng Zhang 6,  Huajun Feng 9,  Jianli Wang 1 2,  Zhenzhai Cai 10,  Zhijian Cai 4
Affiliations

Affiliations

  • 1 Institute of Immunology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 2 Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China.
  • 3 Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, China.
  • 4 Institute of Immunology and Department of Orthopaedics of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 5 Laboratory of Cancer Biology, Key lab of Biotherapy in Zhejiang, Cancer Center of Zhejiang University, Sir Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, Zhejiang, China.
  • 6 Department of Critical Care Medicine of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 7 Department of Abdominal Surgery, Zhejiang Cancer Hospital, Hangzhou, China.
  • 8 Department of Clinical Laboratory, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Clinical Research Center for Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, China.
  • 9 Ecological-Environment & Health College, Zhejiang A & F University, Hangzhou, China.
  • 10 Department of Gastroenterology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
  • # Contributed equally.
PMID: 38532609 DOI: 10.1002/jev2.12426
Abstract

Besides participating in diverse pathological and physiological processes, extracellular vesicles (EVs) are also excellent drug-delivery vehicles. However, clinical drugs modulating EV levels are still lacking. Here, we show that Proton Pump inhibitors (PPIs) reduce EVs by enhancing macropinocytosis-mediated EV uptake. PPIs accelerate intestinal cell endocytosis of autocrine immunosuppressive EVs through macropinocytosis, thereby aggravating inflammatory bowel disease. PPI-induced macropinocytosis facilitates the clearance of immunosuppressive EVs from tumour cells, improving antitumor immunity. PPI-induced macropinocytosis also increases doxorubicin and Antisense Oligonucleotides of microRNA-155 delivery efficiency by EVs, leading to enhanced therapeutic effects of drug-loaded EVs on tumours and acute liver failure. Mechanistically, PPIs reduce cytosolic pH, promote ATP6V1A (v-ATPase subunit) disassembly from the vacuolar membrane and enhance the assembly of plasma membrane v-ATPases, thereby inducing macropinocytosis. Altogether, our results reveal a mechanism for macropinocytic regulation and PPIs as potential modulators of EV levels, thus regulating their functions.

Keywords

extracellular vesicles; macropinocytosis; pH; proton pump inhibitors; v‐ATPases.

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