TY - JOUR
T1 - SNAP23-Mediated Perturbation of Cholesterol-Enriched Membrane Microdomain Promotes Extracellular Vesicle Production in Src-Activated Cancer Cells
AU - Mitani, Fumie
AU - Hayasaka, Ryosuke
AU - Hirayama, Akiyoshi
AU - Oneyama, Chitose
N1 - Funding Information:
We thank Ms. S. Ikeda and M. Hasebe for their technical assistance at Keio University. This work was supported by JST, CREST (JPMJCR17H4 to C.O.), and a Grant-in-Aid for Scientific Research (B) (20H03456 to C.O.), Advanced Genome Research and Bioinformatics Study to Facilitate Medical Innovation (GRIFIN) from the AMED (JP18km0405209 to A.H.).
Publisher Copyright:
© 2022 The Pharmaceutical Society of Japan.
PY - 2022/10
Y1 - 2022/10
N2 - Extracellular vesicles (EVs) originating from intraluminal vesicles (ILVs) formed within multivesicular bodies (MVBs), often referred to as small EV (sEV) or exosomes, are aberrantly produced by cancer cells and regulate the tumor microenvironment. The tyrosine kinase c-Src is upregulated in a wide variety of human cancers and is involved in promoting sEV secretion, suggesting its role in malignant progression. In this study, we found that activated Src liberated synaptosomal-associated protein 23 (SNAP23), a SNARE molecule, from lipid rafts to non-rafts on cellular membrane. We also demonstrated that SNAP23 localized in non-rafts induced cholesterol downregulation and ILV formation, resulting in the upregulation of sEV production in c-Src-transformed cells. Furthermore, the contribution of the SNAP23-cholesterol axis on sEV upregulation was confirmed in pancreatic cancer cells. High SNAP23 expression is associated with poor prognosis in patients with pancreatic cancer. These findings suggest a unique mechanism for the upregulation of sEV production via SNAP23-mediated cholesterol downregulation in Src-activated cancer cells.
AB - Extracellular vesicles (EVs) originating from intraluminal vesicles (ILVs) formed within multivesicular bodies (MVBs), often referred to as small EV (sEV) or exosomes, are aberrantly produced by cancer cells and regulate the tumor microenvironment. The tyrosine kinase c-Src is upregulated in a wide variety of human cancers and is involved in promoting sEV secretion, suggesting its role in malignant progression. In this study, we found that activated Src liberated synaptosomal-associated protein 23 (SNAP23), a SNARE molecule, from lipid rafts to non-rafts on cellular membrane. We also demonstrated that SNAP23 localized in non-rafts induced cholesterol downregulation and ILV formation, resulting in the upregulation of sEV production in c-Src-transformed cells. Furthermore, the contribution of the SNAP23-cholesterol axis on sEV upregulation was confirmed in pancreatic cancer cells. High SNAP23 expression is associated with poor prognosis in patients with pancreatic cancer. These findings suggest a unique mechanism for the upregulation of sEV production via SNAP23-mediated cholesterol downregulation in Src-activated cancer cells.
KW - Src
KW - cholesterol
KW - intraluminal vesicle
KW - raft
KW - small extracellular vesicle
KW - synaptosomal-associated protein 23
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U2 - 10.1248/bpb.b22-00560
DO - 10.1248/bpb.b22-00560
M3 - Article
C2 - 36184518
AN - SCOPUS:85139162985
SN - 0918-6158
VL - 45
SP - 1572
EP - 1580
JO - Biological and Pharmaceutical Bulletin
JF - Biological and Pharmaceutical Bulletin
IS - 10
ER -
