MAGE-A inhibits apoptosis in proliferating myeloma cells through repression of Bax and maintenance of survivin. Academic Article uri icon

Overview

MeSH

  • Cell Cycle
  • Cell Line, Tumor
  • Cell Proliferation
  • Disease Progression
  • Female
  • Gene Silencing
  • Humans
  • Male
  • Middle Aged
  • Signal Transduction
  • Tumor Suppressor Protein p53

MeSH Major

  • Antigens, Neoplasm
  • Apoptosis
  • Gene Expression Regulation, Neoplastic
  • Inhibitor of Apoptosis Proteins
  • Multiple Myeloma
  • Neoplasm Proteins
  • bcl-2-Associated X Protein

abstract

  • The type I Melanoma Antigen GEnes (MAGEs) are commonly expressed in cancers, fueling speculation that they may be therapeutic targets with oncogenic potential. They form complexes with RING domain proteins that have E3 ubiquitin ligase activity and promote p53 degradation. MAGE-A3 was detected in tumor specimens from patients with multiple myeloma and its expression correlated with higher frequencies of Ki-67(+) malignant cells. In this report, we examine the mechanistic role of MAGE-A in promoting survival of proliferating multiple myeloma cells. The impact of MAGE-A3 expression on survival and proliferation in vivo was examined by immunohistochemical analysis in an independent set of tumor specimens segregated into two groups: newly diagnosed, untreated patients and patients who had relapsed after chemotherapy. The mechanisms of MAGE-A3 activity were investigated in vitro by silencing its expression by short hairpin RNA interference in myeloma cell lines and primary cells and assessing the resultant effects on proliferation and apoptosis. MAGE-A3 was detected in a significantly higher percentage of relapsed patients compared with newly diagnosed, establishing a novel correlation with progression of disease. Silencing of MAGE-A showed that it was dispensable for cell cycling, but was required for survival of proliferating myeloma cells. Loss of MAGE-A led to apoptosis mediated by p53-dependent activation of proapoptotic Bax expression and by reduction of survivin expression through both p53-dependent and -independent mechanisms. These data support a role for MAGE-A in the pathogenesis and progression of multiple myeloma by inhibiting apoptosis in proliferating myeloma cells through two novel mechanisms.

publication date

  • July 1, 2011

has subject area

  • Antigens, Neoplasm
  • Apoptosis
  • Cell Cycle
  • Cell Line, Tumor
  • Cell Proliferation
  • Disease Progression
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • Humans
  • Inhibitor of Apoptosis Proteins
  • Male
  • Middle Aged
  • Multiple Myeloma
  • Neoplasm Proteins
  • Signal Transduction
  • Tumor Suppressor Protein p53
  • bcl-2-Associated X Protein

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3131419

Digital Object Identifier (DOI)

  • 10.1158/1078-0432.CCR-10-1820

PubMed ID

  • 21565982

Additional Document Info

start page

  • 4309

end page

  • 4319

volume

  • 17

number

  • 13