Expression of nuclear XIAP associates with cell growth and drug resistance and confers poor prognosis in breast cancer

Biochim Biophys Acta Mol Cell Res. 2020 Oct;1867(10):118761. doi: 10.1016/j.bbamcr.2020.118761. Epub 2020 May 30.

Abstract

Evasion from apoptosis is one of the hallmarks of cancer. X-linked inhibitor of apoptosis protein (XIAP) is known to modulate apoptosis by inhibiting caspases and ubiquitinating target proteins. XIAP is mainly found at the cytoplasm, but recent data link nuclear XIAP to poor prognosis in breast cancer. Here, we generated a mutant form of XIAP with a nuclear localization signal (XIAPNLS-C-term) and investigated the oncogenic mechanisms associated with nuclear XIAP in breast cancer. Our results show that cells overexpressing XIAPΔRING (RING deletion) and XIAPNLS-C-term exhibited XIAP nuclear localization more abundantly than XIAPwild-type. Remarkably, overexpression of XIAPNLS-C-term, but not XIAPΔRING, conferred resistance to doxorubicin and increased cellular proliferative capacity. Interestingly, Survivin and c-IAP1 expression were not associated with XIAP oncogenic effects. However, NFκB expression and ubiquitination of K63, but not K48 chains, were increased following XIAPNLS-C-term overexpression, pointing to nuclear signaling transduction. Consistently, multivariate analysis revealed nuclear, but not cytoplasmic XIAP, as an independent prognostic factor in hormone receptor-negative breast cancer patients. Altogether, our findings suggest that nuclear XIAP confers poor outcome and RING-associated breast cancer growth and chemoresistance.

Keywords: Breast cancer; Drug resistance; Prognosis; Subcellular localization; XIAP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology*
  • Carcinoma, Ductal, Breast / genetics
  • Carcinoma, Ductal, Breast / pathology
  • Cell Line, Tumor
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism*
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Doxorubicin / pharmacology
  • Drug Resistance, Neoplasm* / drug effects
  • Drug Resistance, Neoplasm* / genetics
  • Female
  • Gene Expression Regulation, Neoplastic* / drug effects
  • HEK293 Cells
  • Humans
  • Lysine / metabolism
  • Multivariate Analysis
  • Mutant Proteins / metabolism
  • Mutation / genetics
  • NF-kappa B / metabolism
  • Polyubiquitin / metabolism
  • Prognosis
  • Protein Domains
  • Receptors, Cell Surface / metabolism
  • Survival Analysis
  • Ubiquitination / drug effects
  • X-Linked Inhibitor of Apoptosis Protein / chemistry
  • X-Linked Inhibitor of Apoptosis Protein / metabolism*

Substances

  • Mutant Proteins
  • NF-kappa B
  • Receptors, Cell Surface
  • X-Linked Inhibitor of Apoptosis Protein
  • Polyubiquitin
  • Doxorubicin
  • Lysine