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

Nao Nishimura, Mohamed O. Radwan, Masayuki Amano, Shinya Endo, Eri Fujii, Hironori Hayashi, Shikiko Ueno, Niina Ueno, Hiro Tatetsu, Hiroyuki Hata, Yoshinari Okamoto, Masami Otsuka, Hiroaki Mitsuya, Masao Matsuoka, Yutaka Okuno

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

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 (IC50, 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. IC50 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.

Original languageEnglish
Pages (from-to)3275-3287
Number of pages13
JournalCancer science
Volume110
Issue number10
DOIs
Publication statusPublished - 2019 Oct 1
Externally publishedYes

Keywords

  • ERAD
  • OSSL_320596
  • apoptosis
  • myeloma
  • p97/VCP

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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