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ID 58568
フルテキストURL
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著者
Eguchi, Takanori Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University ORCID Kaken ID researchmap
Sogawa, Chiharu Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University ORCID Kaken ID publons researchmap
Ono, Kisho Department of Oral and Maxillofacial Surgery, Okayama University Hospital
Matsumoto, Masaki Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University
Manh Tien, Tran Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
Okusha, Yuka Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kaken ID researchmap
Lang, Benjamin J. Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School
Okamoto, Kuniaki Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
Calderwood, Stuart K. Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School
抄録
Tumor cells exhibit therapeutic stress resistance-associated secretory phenotype involving extracellular vesicles (EVs) such as oncosomes and heat shock proteins (HSPs). Such a secretory phenotype occurs in response to cell stress and cancer therapeutics. HSPs are stress-responsive molecular chaperones promoting proper protein folding, while also being released from cells with EVs as well as a soluble form known as alarmins. We have here investigated the secretory phenotype of castration-resistant prostate cancer (CRPC) cells using proteome analysis. We have also examined the roles of the key co-chaperone CDC37 in the release of EV proteins including CD9 and epithelial-to-mesenchymal transition (EMT), a key event in tumor progression. EVs derived from CRPC cells promoted EMT in normal prostate epithelial cells. Some HSP family members and their potential receptor CD91/LRP1 were enriched at high levels in CRPC cell-derived EVs among over 700 other protein types found by mass spectrometry. The small EVs (30-200 nm in size) were released even in a non-heated condition from the prostate cancer cells, whereas the EMT-coupled release of EVs (200-500 nm) and damaged membrane vesicles with associated HSP90 alpha was increased after heat shock stress (HSS). GAPDH and lactate dehydrogenase, a marker of membrane leakage/damage, were also found in conditioned media upon HSS. During this stress response, the intracellular chaperone CDC37 was transcriptionally induced by heat shock factor 1 (HSF1), which activated the CDC37 core promoter, containing an interspecies conserved heat shock element. In contrast, knockdown of CDC37 decreased EMT-coupled release of CD9-containing vesicles. Triple siRNA targeting CDC37, HSP90 alpha, and HSP90 beta was required for efficient reduction of this chaperone trio and to reduce tumorigenicity of the CRPC cells in vivo. Taken together, we define "stressome" as cellular stress-induced all secretion products, including EVs (200-500 nm), membrane-damaged vesicles and remnants, and extracellular HSP90 and GAPDH. Our data also indicated that CDC37 is crucial for the release of vesicular proteins and tumor progression in prostate cancer.
キーワード
cell stress response
stressome
extracellular vesicle
heat shock protein 90 (HSP90)
cell division control 37 (CDC37)
prostate cancer
exosome
ectosome
発行日
2020-03-19
出版物タイトル
Cells
9巻
3号
出版者
MDPI
開始ページ
755
ISSN
2073-4409
資料タイプ
学術雑誌論文
言語
English
OAI-PMH Set
岡山大学
著作権者
© 2020 by the authors.
論文のバージョン
publisher
PubMed ID
DOI
Web of Science KeyUT
関連URL
isVersionOf https://doi.org/10.3390/cells9030755
ライセンス
http://creativecommons.org/licenses/by/4.0/
Citation
Eguchi T, Sogawa C, Ono K, et al. Cell Stress Induced Stressome Release Including Damaged Membrane Vesicles and Extracellular HSP90 by Prostate Cancer Cells. Cells. 2020;9(3):755. Published 2020 Mar 19. doi:10.3390/cells9030755
助成機関名
日本学術振興会