Novel p97/VCP inhibitor induces endoplasmic reticulum stress and apoptosis in both bortezomib‐sensitive and ‐resistant multiple myeloma cells

Autor: Hiroaki Mitsuya, Yutaka Okuno, Niina Ueno, Masao Matsuoka, Masami Otsuka, Masayuki Amano, Mohamed O. Radwan, Hironori Hayashi, Eri Fujii, Shinya Endo, Hiroyuki Hata, Yoshinari Okamoto, Shikiko Ueno, Hiro Tatetsu, Nao Nishimura
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
Models
Molecular
Cancer Research
ATPase
Endoplasmic Reticulum
Bortezomib
Mice
eIF-2 Kinase
0302 clinical medicine
Enzyme Inhibitors
Adenosine Triphosphatases
biology
Chemistry
apoptosis
Nuclear Proteins
General Medicine
Endoplasmic Reticulum Stress
AAA proteins
myeloma
Oncology
p97/VCP
030220 oncology & carcinogenesis
Original Article
Female
Multiple Myeloma
medicine.drug
Cell Survival
Protein degradation
Protein Serine-Threonine Kinases
Small Molecule Libraries
03 medical and health sciences
Cell Line
Tumor
Endoribonucleases
medicine
Animals
Humans
Cell Proliferation
Binding Sites
Endoplasmic reticulum
Ubiquitination
Original Articles
OSSL_320596
ERAD
Molecular biology
Xenograft Model Antitumor Assays
030104 developmental biology
Drug Discovery and Delivery
Apoptosis
Cell culture
Drug Resistance
Neoplasm
biology.protein
Unfolded protein response
Drug Screening Assays
Antitumor
Transcription Factor CHOP
Zdroj: Cancer Science
ISSN: 1349-7006
1347-9032
Popis: p97/VCP is an endoplasmic reticulum (ER)‐associated protein that belongs to the AAA (ATPases associated with diverse cellular activities) ATPase family. It has a variety of cellular functions including ER‐associated protein degradation, autophagy, and aggresome formation. Recent studies have shown emerging roles of p97/VCP and its potential as a therapeutic target in several cancer subtypes including multiple myeloma (MM). We conducted a cell‐based compound screen to exploit novel small compounds that have cytotoxic activity in myeloma cells. Among approximately 2000 compounds, OSSL_325096 showed relatively strong antiproliferative activity in MM cell lines (IC 50, 100‐500 nmol/L). OSSL_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, PERK, CHOP, and IREα, was observed in MM cell lines treated with OSSL_325096, suggesting that it induces ER stress in MM cells. OSSL_325096 has a similar chemical structure to DBeQ, a known p97/VCP inhibitor. Knockdown of the gene encoding p97/VCP induced apoptosis in myeloma cells, accompanied by accumulation of poly‐ubiquitinated protein. IC 50 of OSSL_325096 to myeloma cell lines were found to be lower (0.1‐0.8 μmol/L) than those of DBeQ (2‐5 μmol/L). In silico protein–drug‐binding simulation suggested possible binding of OSSL_325096 to the ATP binding site in the D2 domain of p97/VCP. In cell‐free ATPase assays, OSSL_325096 showed dose‐dependent inhibition of p97/VCP ATPase activity. Finally, OSSL_325096 inhibited the growth of subcutaneous myeloma cell tumors in vivo. The present data suggest that OSSL_325096 exerts anti‐myeloma activity, at least in part through p97/VCP inhibition.
Databáze: OpenAIRE
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