author_facet Nishimura, Nao
Radwan, Mohamed O.
Amano, Masayuki
Endo, Shinya
Fujii, Eri
Hayashi, Hironori
Ueno, Shikiko
Ueno, Niina
Tatetsu, Hiro
Hata, Hiroyuki
Okamoto, Yoshinari
Otsuka, Masami
Mitsuya, Hiroaki
Matsuoka, Masao
Okuno, Yutaka
Nishimura, Nao
Radwan, Mohamed O.
Amano, Masayuki
Endo, Shinya
Fujii, Eri
Hayashi, Hironori
Ueno, Shikiko
Ueno, Niina
Tatetsu, Hiro
Hata, Hiroyuki
Okamoto, Yoshinari
Otsuka, Masami
Mitsuya, Hiroaki
Matsuoka, Masao
Okuno, Yutaka
author Nishimura, Nao
Radwan, Mohamed O.
Amano, Masayuki
Endo, Shinya
Fujii, Eri
Hayashi, Hironori
Ueno, Shikiko
Ueno, Niina
Tatetsu, Hiro
Hata, Hiroyuki
Okamoto, Yoshinari
Otsuka, Masami
Mitsuya, Hiroaki
Matsuoka, Masao
Okuno, Yutaka
spellingShingle Nishimura, Nao
Radwan, Mohamed O.
Amano, Masayuki
Endo, Shinya
Fujii, Eri
Hayashi, Hironori
Ueno, Shikiko
Ueno, Niina
Tatetsu, Hiro
Hata, Hiroyuki
Okamoto, Yoshinari
Otsuka, Masami
Mitsuya, Hiroaki
Matsuoka, Masao
Okuno, Yutaka
Cancer Science
Novel p97/VCP inhibitor induces endoplasmic reticulum stress and apoptosis in both bortezomib‐sensitive and ‐resistant multiple myeloma cells
Cancer Research
Oncology
General Medicine
author_sort nishimura, nao
spelling Nishimura, Nao Radwan, Mohamed O. Amano, Masayuki Endo, Shinya Fujii, Eri Hayashi, Hironori Ueno, Shikiko Ueno, Niina Tatetsu, Hiro Hata, Hiroyuki Okamoto, Yoshinari Otsuka, Masami Mitsuya, Hiroaki Matsuoka, Masao Okuno, Yutaka 1347-9032 1349-7006 Wiley Cancer Research Oncology General Medicine http://dx.doi.org/10.1111/cas.14154 <jats:title>Abstract</jats:title><jats:p>p97/<jats:styled-content style="fixed-case">VCP</jats:styled-content> is an endoplasmic reticulum (<jats:styled-content style="fixed-case">ER</jats:styled-content>)‐associated protein that belongs to the <jats:styled-content style="fixed-case">AAA</jats:styled-content> (<jats:styled-content style="fixed-case">ATP</jats:styled-content>ases associated with diverse cellular activities) <jats:styled-content style="fixed-case">ATP</jats:styled-content>ase family. It has a variety of cellular functions including <jats:styled-content style="fixed-case">ER</jats:styled-content>‐associated protein degradation, autophagy, and aggresome formation. Recent studies have shown emerging roles of p97/<jats:styled-content style="fixed-case">VCP</jats:styled-content> and its potential as a therapeutic target in several cancer subtypes including multiple myeloma (<jats:styled-content style="fixed-case">MM</jats:styled-content>). We conducted a cell‐based compound screen to exploit novel small compounds that have cytotoxic activity in myeloma cells. Among approximately 2000 compounds, <jats:styled-content style="fixed-case">OSSL</jats:styled-content>_325096 showed relatively strong antiproliferative activity in <jats:styled-content style="fixed-case">MM</jats:styled-content> cell lines (<jats:styled-content style="fixed-case">IC</jats:styled-content><jats:sub>50</jats:sub>, 100‐500 nmol/L). <jats:styled-content style="fixed-case">OSSL</jats:styled-content>_325096 induced apoptosis in myeloma cell lines, including a bortezomib‐resistant cell line and primary myeloma cells purified from patients. Accumulation of poly‐ubiquitinated proteins, <jats:styled-content style="fixed-case">PERK</jats:styled-content>,<jats:styled-content style="fixed-case"> CHOP</jats:styled-content>, and <jats:styled-content style="fixed-case">IRE</jats:styled-content>α, was observed in <jats:styled-content style="fixed-case">MM</jats:styled-content> cell lines treated with <jats:styled-content style="fixed-case">OSSL</jats:styled-content>_325096, suggesting that it induces <jats:styled-content style="fixed-case">ER</jats:styled-content> stress in <jats:styled-content style="fixed-case">MM</jats:styled-content> cells. <jats:styled-content style="fixed-case">OSSL</jats:styled-content>_325096 has a similar chemical structure to <jats:styled-content style="fixed-case">DB</jats:styled-content>eQ, a known p97/<jats:styled-content style="fixed-case">VCP</jats:styled-content> inhibitor. Knockdown of the gene encoding p97/<jats:styled-content style="fixed-case">VCP</jats:styled-content> induced apoptosis in myeloma cells, accompanied by accumulation of poly‐ubiquitinated protein. <jats:styled-content style="fixed-case">IC</jats:styled-content><jats:sub>50</jats:sub> of <jats:styled-content style="fixed-case">OSSL</jats:styled-content>_325096 to myeloma cell lines were found to be lower (0.1‐0.8 μmol/L) than those of <jats:styled-content style="fixed-case">DB</jats:styled-content>eQ (2‐5 μmol/L). In silico protein–drug‐binding simulation suggested possible binding of <jats:styled-content style="fixed-case">OSSL</jats:styled-content>_325096 to the <jats:styled-content style="fixed-case">ATP</jats:styled-content> binding site in the D2 domain of p97/<jats:styled-content style="fixed-case">VCP</jats:styled-content>. In cell‐free <jats:styled-content style="fixed-case">ATP</jats:styled-content>ase assays, <jats:styled-content style="fixed-case">OSSL</jats:styled-content>_325096 showed dose‐dependent inhibition of p97/<jats:styled-content style="fixed-case">VCP ATP</jats:styled-content>ase activity. Finally, <jats:styled-content style="fixed-case">OSSL</jats:styled-content>_325096 inhibited the growth of subcutaneous myeloma cell tumors in vivo. The present data suggest that <jats:styled-content style="fixed-case">OSSL</jats:styled-content>_325096 exerts anti‐myeloma activity, at least in part through p97/<jats:styled-content style="fixed-case">VCP</jats:styled-content> inhibition.</jats:p> Novel p97/<scp>VCP</scp> inhibitor induces endoplasmic reticulum stress and apoptosis in both bortezomib‐sensitive and ‐resistant multiple myeloma cells Cancer Science
doi_str_mv 10.1111/cas.14154
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match_str nishimura2019novelp97vcpinhibitorinducesendoplasmicreticulumstressandapoptosisinbothbortezomibsensitiveandresistantmultiplemyelomacells
publishDateSort 2019
publisher Wiley
recordtype ai
record_format ai
series Cancer Science
source_id 49
title Novel p97/VCP inhibitor induces endoplasmic reticulum stress and apoptosis in both bortezomib‐sensitive and ‐resistant multiple myeloma cells
title_unstemmed Novel p97/VCP inhibitor induces endoplasmic reticulum stress and apoptosis in both bortezomib‐sensitive and ‐resistant multiple myeloma cells
title_full Novel p97/VCP inhibitor induces endoplasmic reticulum stress and apoptosis in both bortezomib‐sensitive and ‐resistant multiple myeloma cells
title_fullStr Novel p97/VCP inhibitor induces endoplasmic reticulum stress and apoptosis in both bortezomib‐sensitive and ‐resistant multiple myeloma cells
title_full_unstemmed Novel p97/VCP inhibitor induces endoplasmic reticulum stress and apoptosis in both bortezomib‐sensitive and ‐resistant multiple myeloma cells
title_short Novel p97/VCP inhibitor induces endoplasmic reticulum stress and apoptosis in both bortezomib‐sensitive and ‐resistant multiple myeloma cells
title_sort novel p97/<scp>vcp</scp> inhibitor induces endoplasmic reticulum stress and apoptosis in both bortezomib‐sensitive and ‐resistant multiple myeloma cells
topic Cancer Research
Oncology
General Medicine
url http://dx.doi.org/10.1111/cas.14154
publishDate 2019
physical 3275-3287
description <jats:title>Abstract</jats:title><jats:p>p97/<jats:styled-content style="fixed-case">VCP</jats:styled-content> is an endoplasmic reticulum (<jats:styled-content style="fixed-case">ER</jats:styled-content>)‐associated protein that belongs to the <jats:styled-content style="fixed-case">AAA</jats:styled-content> (<jats:styled-content style="fixed-case">ATP</jats:styled-content>ases associated with diverse cellular activities) <jats:styled-content style="fixed-case">ATP</jats:styled-content>ase family. It has a variety of cellular functions including <jats:styled-content style="fixed-case">ER</jats:styled-content>‐associated protein degradation, autophagy, and aggresome formation. Recent studies have shown emerging roles of p97/<jats:styled-content style="fixed-case">VCP</jats:styled-content> and its potential as a therapeutic target in several cancer subtypes including multiple myeloma (<jats:styled-content style="fixed-case">MM</jats:styled-content>). We conducted a cell‐based compound screen to exploit novel small compounds that have cytotoxic activity in myeloma cells. Among approximately 2000 compounds, <jats:styled-content style="fixed-case">OSSL</jats:styled-content>_325096 showed relatively strong antiproliferative activity in <jats:styled-content style="fixed-case">MM</jats:styled-content> cell lines (<jats:styled-content style="fixed-case">IC</jats:styled-content><jats:sub>50</jats:sub>, 100‐500 nmol/L). <jats:styled-content style="fixed-case">OSSL</jats:styled-content>_325096 induced apoptosis in myeloma cell lines, including a bortezomib‐resistant cell line and primary myeloma cells purified from patients. Accumulation of poly‐ubiquitinated proteins, <jats:styled-content style="fixed-case">PERK</jats:styled-content>,<jats:styled-content style="fixed-case"> CHOP</jats:styled-content>, and <jats:styled-content style="fixed-case">IRE</jats:styled-content>α, was observed in <jats:styled-content style="fixed-case">MM</jats:styled-content> cell lines treated with <jats:styled-content style="fixed-case">OSSL</jats:styled-content>_325096, suggesting that it induces <jats:styled-content style="fixed-case">ER</jats:styled-content> stress in <jats:styled-content style="fixed-case">MM</jats:styled-content> cells. <jats:styled-content style="fixed-case">OSSL</jats:styled-content>_325096 has a similar chemical structure to <jats:styled-content style="fixed-case">DB</jats:styled-content>eQ, a known p97/<jats:styled-content style="fixed-case">VCP</jats:styled-content> inhibitor. Knockdown of the gene encoding p97/<jats:styled-content style="fixed-case">VCP</jats:styled-content> induced apoptosis in myeloma cells, accompanied by accumulation of poly‐ubiquitinated protein. <jats:styled-content style="fixed-case">IC</jats:styled-content><jats:sub>50</jats:sub> of <jats:styled-content style="fixed-case">OSSL</jats:styled-content>_325096 to myeloma cell lines were found to be lower (0.1‐0.8 μmol/L) than those of <jats:styled-content style="fixed-case">DB</jats:styled-content>eQ (2‐5 μmol/L). In silico protein–drug‐binding simulation suggested possible binding of <jats:styled-content style="fixed-case">OSSL</jats:styled-content>_325096 to the <jats:styled-content style="fixed-case">ATP</jats:styled-content> binding site in the D2 domain of p97/<jats:styled-content style="fixed-case">VCP</jats:styled-content>. In cell‐free <jats:styled-content style="fixed-case">ATP</jats:styled-content>ase assays, <jats:styled-content style="fixed-case">OSSL</jats:styled-content>_325096 showed dose‐dependent inhibition of p97/<jats:styled-content style="fixed-case">VCP ATP</jats:styled-content>ase activity. Finally, <jats:styled-content style="fixed-case">OSSL</jats:styled-content>_325096 inhibited the growth of subcutaneous myeloma cell tumors in vivo. The present data suggest that <jats:styled-content style="fixed-case">OSSL</jats:styled-content>_325096 exerts anti‐myeloma activity, at least in part through p97/<jats:styled-content style="fixed-case">VCP</jats:styled-content> inhibition.</jats:p>
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author Nishimura, Nao, Radwan, Mohamed O., Amano, Masayuki, Endo, Shinya, Fujii, Eri, Hayashi, Hironori, Ueno, Shikiko, Ueno, Niina, Tatetsu, Hiro, Hata, Hiroyuki, Okamoto, Yoshinari, Otsuka, Masami, Mitsuya, Hiroaki, Matsuoka, Masao, Okuno, Yutaka
author_facet Nishimura, Nao, Radwan, Mohamed O., Amano, Masayuki, Endo, Shinya, Fujii, Eri, Hayashi, Hironori, Ueno, Shikiko, Ueno, Niina, Tatetsu, Hiro, Hata, Hiroyuki, Okamoto, Yoshinari, Otsuka, Masami, Mitsuya, Hiroaki, Matsuoka, Masao, Okuno, Yutaka, Nishimura, Nao, Radwan, Mohamed O., Amano, Masayuki, Endo, Shinya, Fujii, Eri, Hayashi, Hironori, Ueno, Shikiko, Ueno, Niina, Tatetsu, Hiro, Hata, Hiroyuki, Okamoto, Yoshinari, Otsuka, Masami, Mitsuya, Hiroaki, Matsuoka, Masao, Okuno, Yutaka
author_sort nishimura, nao
container_issue 10
container_start_page 3275
container_title Cancer Science
container_volume 110
description <jats:title>Abstract</jats:title><jats:p>p97/<jats:styled-content style="fixed-case">VCP</jats:styled-content> is an endoplasmic reticulum (<jats:styled-content style="fixed-case">ER</jats:styled-content>)‐associated protein that belongs to the <jats:styled-content style="fixed-case">AAA</jats:styled-content> (<jats:styled-content style="fixed-case">ATP</jats:styled-content>ases associated with diverse cellular activities) <jats:styled-content style="fixed-case">ATP</jats:styled-content>ase family. It has a variety of cellular functions including <jats:styled-content style="fixed-case">ER</jats:styled-content>‐associated protein degradation, autophagy, and aggresome formation. Recent studies have shown emerging roles of p97/<jats:styled-content style="fixed-case">VCP</jats:styled-content> and its potential as a therapeutic target in several cancer subtypes including multiple myeloma (<jats:styled-content style="fixed-case">MM</jats:styled-content>). We conducted a cell‐based compound screen to exploit novel small compounds that have cytotoxic activity in myeloma cells. Among approximately 2000 compounds, <jats:styled-content style="fixed-case">OSSL</jats:styled-content>_325096 showed relatively strong antiproliferative activity in <jats:styled-content style="fixed-case">MM</jats:styled-content> cell lines (<jats:styled-content style="fixed-case">IC</jats:styled-content><jats:sub>50</jats:sub>, 100‐500 nmol/L). <jats:styled-content style="fixed-case">OSSL</jats:styled-content>_325096 induced apoptosis in myeloma cell lines, including a bortezomib‐resistant cell line and primary myeloma cells purified from patients. Accumulation of poly‐ubiquitinated proteins, <jats:styled-content style="fixed-case">PERK</jats:styled-content>,<jats:styled-content style="fixed-case"> CHOP</jats:styled-content>, and <jats:styled-content style="fixed-case">IRE</jats:styled-content>α, was observed in <jats:styled-content style="fixed-case">MM</jats:styled-content> cell lines treated with <jats:styled-content style="fixed-case">OSSL</jats:styled-content>_325096, suggesting that it induces <jats:styled-content style="fixed-case">ER</jats:styled-content> stress in <jats:styled-content style="fixed-case">MM</jats:styled-content> cells. <jats:styled-content style="fixed-case">OSSL</jats:styled-content>_325096 has a similar chemical structure to <jats:styled-content style="fixed-case">DB</jats:styled-content>eQ, a known p97/<jats:styled-content style="fixed-case">VCP</jats:styled-content> inhibitor. Knockdown of the gene encoding p97/<jats:styled-content style="fixed-case">VCP</jats:styled-content> induced apoptosis in myeloma cells, accompanied by accumulation of poly‐ubiquitinated protein. <jats:styled-content style="fixed-case">IC</jats:styled-content><jats:sub>50</jats:sub> of <jats:styled-content style="fixed-case">OSSL</jats:styled-content>_325096 to myeloma cell lines were found to be lower (0.1‐0.8 μmol/L) than those of <jats:styled-content style="fixed-case">DB</jats:styled-content>eQ (2‐5 μmol/L). In silico protein–drug‐binding simulation suggested possible binding of <jats:styled-content style="fixed-case">OSSL</jats:styled-content>_325096 to the <jats:styled-content style="fixed-case">ATP</jats:styled-content> binding site in the D2 domain of p97/<jats:styled-content style="fixed-case">VCP</jats:styled-content>. In cell‐free <jats:styled-content style="fixed-case">ATP</jats:styled-content>ase assays, <jats:styled-content style="fixed-case">OSSL</jats:styled-content>_325096 showed dose‐dependent inhibition of p97/<jats:styled-content style="fixed-case">VCP ATP</jats:styled-content>ase activity. Finally, <jats:styled-content style="fixed-case">OSSL</jats:styled-content>_325096 inhibited the growth of subcutaneous myeloma cell tumors in vivo. The present data suggest that <jats:styled-content style="fixed-case">OSSL</jats:styled-content>_325096 exerts anti‐myeloma activity, at least in part through p97/<jats:styled-content style="fixed-case">VCP</jats:styled-content> inhibition.</jats:p>
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source_id 49
spelling Nishimura, Nao Radwan, Mohamed O. Amano, Masayuki Endo, Shinya Fujii, Eri Hayashi, Hironori Ueno, Shikiko Ueno, Niina Tatetsu, Hiro Hata, Hiroyuki Okamoto, Yoshinari Otsuka, Masami Mitsuya, Hiroaki Matsuoka, Masao Okuno, Yutaka 1347-9032 1349-7006 Wiley Cancer Research Oncology General Medicine http://dx.doi.org/10.1111/cas.14154 <jats:title>Abstract</jats:title><jats:p>p97/<jats:styled-content style="fixed-case">VCP</jats:styled-content> is an endoplasmic reticulum (<jats:styled-content style="fixed-case">ER</jats:styled-content>)‐associated protein that belongs to the <jats:styled-content style="fixed-case">AAA</jats:styled-content> (<jats:styled-content style="fixed-case">ATP</jats:styled-content>ases associated with diverse cellular activities) <jats:styled-content style="fixed-case">ATP</jats:styled-content>ase family. It has a variety of cellular functions including <jats:styled-content style="fixed-case">ER</jats:styled-content>‐associated protein degradation, autophagy, and aggresome formation. Recent studies have shown emerging roles of p97/<jats:styled-content style="fixed-case">VCP</jats:styled-content> and its potential as a therapeutic target in several cancer subtypes including multiple myeloma (<jats:styled-content style="fixed-case">MM</jats:styled-content>). We conducted a cell‐based compound screen to exploit novel small compounds that have cytotoxic activity in myeloma cells. Among approximately 2000 compounds, <jats:styled-content style="fixed-case">OSSL</jats:styled-content>_325096 showed relatively strong antiproliferative activity in <jats:styled-content style="fixed-case">MM</jats:styled-content> cell lines (<jats:styled-content style="fixed-case">IC</jats:styled-content><jats:sub>50</jats:sub>, 100‐500 nmol/L). <jats:styled-content style="fixed-case">OSSL</jats:styled-content>_325096 induced apoptosis in myeloma cell lines, including a bortezomib‐resistant cell line and primary myeloma cells purified from patients. Accumulation of poly‐ubiquitinated proteins, <jats:styled-content style="fixed-case">PERK</jats:styled-content>,<jats:styled-content style="fixed-case"> CHOP</jats:styled-content>, and <jats:styled-content style="fixed-case">IRE</jats:styled-content>α, was observed in <jats:styled-content style="fixed-case">MM</jats:styled-content> cell lines treated with <jats:styled-content style="fixed-case">OSSL</jats:styled-content>_325096, suggesting that it induces <jats:styled-content style="fixed-case">ER</jats:styled-content> stress in <jats:styled-content style="fixed-case">MM</jats:styled-content> cells. <jats:styled-content style="fixed-case">OSSL</jats:styled-content>_325096 has a similar chemical structure to <jats:styled-content style="fixed-case">DB</jats:styled-content>eQ, a known p97/<jats:styled-content style="fixed-case">VCP</jats:styled-content> inhibitor. Knockdown of the gene encoding p97/<jats:styled-content style="fixed-case">VCP</jats:styled-content> induced apoptosis in myeloma cells, accompanied by accumulation of poly‐ubiquitinated protein. <jats:styled-content style="fixed-case">IC</jats:styled-content><jats:sub>50</jats:sub> of <jats:styled-content style="fixed-case">OSSL</jats:styled-content>_325096 to myeloma cell lines were found to be lower (0.1‐0.8 μmol/L) than those of <jats:styled-content style="fixed-case">DB</jats:styled-content>eQ (2‐5 μmol/L). In silico protein–drug‐binding simulation suggested possible binding of <jats:styled-content style="fixed-case">OSSL</jats:styled-content>_325096 to the <jats:styled-content style="fixed-case">ATP</jats:styled-content> binding site in the D2 domain of p97/<jats:styled-content style="fixed-case">VCP</jats:styled-content>. In cell‐free <jats:styled-content style="fixed-case">ATP</jats:styled-content>ase assays, <jats:styled-content style="fixed-case">OSSL</jats:styled-content>_325096 showed dose‐dependent inhibition of p97/<jats:styled-content style="fixed-case">VCP ATP</jats:styled-content>ase activity. Finally, <jats:styled-content style="fixed-case">OSSL</jats:styled-content>_325096 inhibited the growth of subcutaneous myeloma cell tumors in vivo. The present data suggest that <jats:styled-content style="fixed-case">OSSL</jats:styled-content>_325096 exerts anti‐myeloma activity, at least in part through p97/<jats:styled-content style="fixed-case">VCP</jats:styled-content> inhibition.</jats:p> Novel p97/<scp>VCP</scp> inhibitor induces endoplasmic reticulum stress and apoptosis in both bortezomib‐sensitive and ‐resistant multiple myeloma cells Cancer Science
spellingShingle Nishimura, Nao, Radwan, Mohamed O., Amano, Masayuki, Endo, Shinya, Fujii, Eri, Hayashi, Hironori, Ueno, Shikiko, Ueno, Niina, Tatetsu, Hiro, Hata, Hiroyuki, Okamoto, Yoshinari, Otsuka, Masami, Mitsuya, Hiroaki, Matsuoka, Masao, Okuno, Yutaka, Cancer Science, Novel p97/VCP inhibitor induces endoplasmic reticulum stress and apoptosis in both bortezomib‐sensitive and ‐resistant multiple myeloma cells, Cancer Research, Oncology, General Medicine
title Novel p97/VCP inhibitor induces endoplasmic reticulum stress and apoptosis in both bortezomib‐sensitive and ‐resistant multiple myeloma cells
title_full Novel p97/VCP inhibitor induces endoplasmic reticulum stress and apoptosis in both bortezomib‐sensitive and ‐resistant multiple myeloma cells
title_fullStr Novel p97/VCP inhibitor induces endoplasmic reticulum stress and apoptosis in both bortezomib‐sensitive and ‐resistant multiple myeloma cells
title_full_unstemmed Novel p97/VCP inhibitor induces endoplasmic reticulum stress and apoptosis in both bortezomib‐sensitive and ‐resistant multiple myeloma cells
title_short Novel p97/VCP inhibitor induces endoplasmic reticulum stress and apoptosis in both bortezomib‐sensitive and ‐resistant multiple myeloma cells
title_sort novel p97/<scp>vcp</scp> inhibitor induces endoplasmic reticulum stress and apoptosis in both bortezomib‐sensitive and ‐resistant multiple myeloma cells
title_unstemmed Novel p97/VCP inhibitor induces endoplasmic reticulum stress and apoptosis in both bortezomib‐sensitive and ‐resistant multiple myeloma cells
topic Cancer Research, Oncology, General Medicine
url http://dx.doi.org/10.1111/cas.14154