Depletion of nucleophosmin via transglutaminase 2 cross-linking increases drug resistance in cancer cells

Kang Seo Park, Byeong Gu Han, Kyoung Hwa Lee, Dae Seok Kim, Jung Mo Kim, Hyesung Jeon, Hyoun Sook Kim, Se Won Suh, Eunjoo H. Lee, Soo Youl Kim, Byung Il Lee

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

It has been suggested that nucleophosmin has an anti-apoptotic function via Bax binding. We found that nucleophosmin is a substrate of transglutaminase 2 (TGase 2) in cancer cells. Increased expression of TGase 2 expression is highly associated with drug resistance, and polymerization of nucleophosmin by TGase 2 also can be correlated with the drug resistance of cancer cells. In the present study, an accumulation of nucleophosmin in cytosol was detected when doxorubicin was treated to cancer cells, and it was found, moreover, that an increase of cytosolic nucleophosmin can result in drug-induced apoptosis. Nucleophosmin was polymerized by TGase 2, and the polymerization was inhibited with the TGase 2 inhibitor, cystamine, in vitro. The nucleophosmin level in the cytosolic cell fraction was reduced when TGase 2 was expressed, and the reduced nucleophosmin level was rescued by cystamine treatment. Moreover, nucleophosmin cross-linked by TGase 2 was eradicated in MCF7 cells via the ubiquitin-proteasomal pathway. In parallel with this nucleophosmin-level restoration, the pro-apoptotic Bax protein level was increased. Therefore, depletion of cytosolic nucleophosmin by TGase 2 can decrease Bax protein stability and lead to anti-apoptosis. Drug-resistant cancer cells became sensitive to doxorubicin treatment when nucleophosmin was expressed in cytosol. Taking these results together, it can be concluded that TGase 2 inhibits accumulation of cytosolic nucleophosmin through polymerization, which results in drug resistance in cancer cells. Crown

Original languageEnglish (US)
Pages (from-to)201-207
Number of pages7
JournalCancer Letters
Volume274
Issue number2
DOIs
StatePublished - Feb 18 2009
Externally publishedYes

Keywords

  • B23
  • Drug resistance
  • Nucleophosmin
  • Polymerization
  • Transglutaminase

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Depletion of nucleophosmin via transglutaminase 2 cross-linking increases drug resistance in cancer cells'. Together they form a unique fingerprint.

Cite this