Ameliorating cancer cachexia by inhibiting cancer cell release of Hsp70 and Hsp90 with omeprazole
© 2021 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders..
BACKGROUND: Cancer cachexia, characterized by muscle and fat tissue wasting, is a major determinant of cancer-related mortality without established treatment. Recent animal data revealed that cancer cells induce muscle wasting by releasing Hsp70 and Hsp90 as surface proteins on extracellular vesicles (EVs). Here, we test a therapeutic strategy for ameliorating cancer cachexia by inhibiting the release of Hsp70 and Hsp90 using proton pump inhibitor omeprazole.
METHODS: Omeprazole effect on Hsp70/90 release through EVs by Lewis lung carcinoma (LLC) cells in vitro, serum levels of Hsp70/90 and Hsp70/90-carrying EVs in LLC tumour-bearing mice, and LLC-induced muscle protein degradation pathways in C2C12 myotubes and mice were determined. Omeprazole effect on endolysosomal pH and Rab27b expression in LLC cells were analysed.
RESULTS: Omeprazole treatment of LLC cells inhibited Hsp70/90 and Hsp70/90-carrying EV release in a dose-dependent manner (1 to 10 μM) and attenuated the catabolic activity of LLC cell-conditioned medium on C2C12 myotubes. Systemic omeprazole administration to LLC tumour-bearing mice (5 mg/kg/day subcutaneously) for 2 weeks blocked elevation of serum Hsp70, Hsp90, and Hsp70/90-carrying EVs, abrogated skeletal muscle catabolism, and prevented loss of muscle function as well as muscle and epididymal fat mass without altering tumour growth. Consequently, median survival increased by 23.3%. Mechanistically, omeprazole increased cancer cell endolysosomal pH level dose-dependently (0.1 to 1 μM) by inhibiting vacuolar H+ -ATPase. Further, omeprazole suppressed the highly elevated expression of Rab27b, a key regulator of EV release, in LLC cells.
CONCLUSIONS: Omeprazole ameliorates cancer cachexia by inhibiting cancer cell release of Hsp70 and Hsp90.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2022 |
|---|---|
| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:13 |
|---|---|
| Enthalten in: |
Journal of cachexia, sarcopenia and muscle - 13(2022), 1 vom: 05. Feb., Seite 636-647 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Liu, Zhelong [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Fat tissue wasting |
|---|
| Anmerkungen: |
Date Completed 23.03.2022 Date Revised 23.03.2022 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1002/jcsm.12851 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM33268122X |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM33268122X | ||
| 003 | DE-627 | ||
| 005 | 20231225220048.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2022 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1002/jcsm.12851 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1108.xml |
| 035 | |a (DE-627)NLM33268122X | ||
| 035 | |a (NLM)34729960 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Liu, Zhelong |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Ameliorating cancer cachexia by inhibiting cancer cell release of Hsp70 and Hsp90 with omeprazole |
| 264 | 1 | |c 2022 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 23.03.2022 | ||
| 500 | |a Date Revised 23.03.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2021 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders. | ||
| 520 | |a BACKGROUND: Cancer cachexia, characterized by muscle and fat tissue wasting, is a major determinant of cancer-related mortality without established treatment. Recent animal data revealed that cancer cells induce muscle wasting by releasing Hsp70 and Hsp90 as surface proteins on extracellular vesicles (EVs). Here, we test a therapeutic strategy for ameliorating cancer cachexia by inhibiting the release of Hsp70 and Hsp90 using proton pump inhibitor omeprazole | ||
| 520 | |a METHODS: Omeprazole effect on Hsp70/90 release through EVs by Lewis lung carcinoma (LLC) cells in vitro, serum levels of Hsp70/90 and Hsp70/90-carrying EVs in LLC tumour-bearing mice, and LLC-induced muscle protein degradation pathways in C2C12 myotubes and mice were determined. Omeprazole effect on endolysosomal pH and Rab27b expression in LLC cells were analysed | ||
| 520 | |a RESULTS: Omeprazole treatment of LLC cells inhibited Hsp70/90 and Hsp70/90-carrying EV release in a dose-dependent manner (1 to 10 μM) and attenuated the catabolic activity of LLC cell-conditioned medium on C2C12 myotubes. Systemic omeprazole administration to LLC tumour-bearing mice (5 mg/kg/day subcutaneously) for 2 weeks blocked elevation of serum Hsp70, Hsp90, and Hsp70/90-carrying EVs, abrogated skeletal muscle catabolism, and prevented loss of muscle function as well as muscle and epididymal fat mass without altering tumour growth. Consequently, median survival increased by 23.3%. Mechanistically, omeprazole increased cancer cell endolysosomal pH level dose-dependently (0.1 to 1 μM) by inhibiting vacuolar H+ -ATPase. Further, omeprazole suppressed the highly elevated expression of Rab27b, a key regulator of EV release, in LLC cells | ||
| 520 | |a CONCLUSIONS: Omeprazole ameliorates cancer cachexia by inhibiting cancer cell release of Hsp70 and Hsp90 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Fat tissue wasting | |
| 650 | 4 | |a Hsp70 | |
| 650 | 4 | |a Hsp90 | |
| 650 | 4 | |a Lewis lung carcinoma | |
| 650 | 4 | |a Muscle wasting | |
| 650 | 4 | |a Rab27b | |
| 650 | 4 | |a Vacuolar H+-ATPase | |
| 650 | 7 | |a Omeprazole |2 NLM | |
| 650 | 7 | |a KG60484QX9 |2 NLM | |
| 700 | 1 | |a Xiong, Jian |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Song |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Michael X |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Kai |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Min |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Guohua |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Yi-Ping |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of cachexia, sarcopenia and muscle |d 2010 |g 13(2022), 1 vom: 05. Feb., Seite 636-647 |w (DE-627)NLM207308543 |x 2190-5991 |7 nnns |
| 773 | 1 | 8 | |g volume:13 |g year:2022 |g number:1 |g day:05 |g month:02 |g pages:636-647 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1002/jcsm.12851 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 13 |j 2022 |e 1 |b 05 |c 02 |h 636-647 | ||