Tumor-associated antigen preferentially expressed antigen of melanoma (PRAME) induces caspase-independent cell death in vitro and reduces tumorigenicity in vivo

Cancer Res. 2005 Aug 15;65(16):7348-55. doi: 10.1158/0008-5472.CAN-04-4011.

Abstract

Preferentially expressed antigen of melanoma (PRAME) is expressed in a wide variety of tumors, but in contrast with most other tumor associated antigens, it is also expressed in leukemias. The physiologic role of PRAME remains elusive. Interestingly, PRAME expression is correlated with a favorable prognosis in childhood acute leukemias. Moreover, a high expression of PRAME seems to be predominantly found in acute leukemias carrying a favorable prognosis. On these clinical observations, we assumed that PRAME could be involved in the regulation of cell death or cell cycle. In this study, we show that transient overexpression of PRAME induces a caspase-independent cell death in cultured cell lines (CHO-K1 and HeLa). Cells stably transfected with PRAME also exhibit a decreased proliferation rate due, at least partially, to an elevated basal rate of cell death. Immunocytochemistry of a FLAG-tagged PRAME, in vivo imaging of an enhanced green fluorescent protein-tagged PRAME, and Western blotting after cell fractionation reveal a nuclear localization of the protein. Using a microarray-based approach, we show that KG-1 leukemic cells stably transfected with PRAME present a significant decrease of expression of the heat-shock protein Hsp27, the cyclin-dependent kinase inhibitor p21, and the calcium-binding protein S100A4. The expression of these three proteins is known to inhibit apoptosis and has been associated with an unfavorable prognosis in a series of cancers. Finally, repression of PRAME expression by a short interfering RNA strategy increases tumorigenicity of K562 leukemic cells in nude mice. We suggest that all these observations might explain the favorable prognosis of the leukemias expressing high levels of PRAME.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm / biosynthesis
  • Antigens, Neoplasm / genetics
  • Antigens, Neoplasm / metabolism
  • Antigens, Neoplasm / physiology*
  • Apoptosis / physiology*
  • CHO Cells
  • Caspases / metabolism
  • Cell Cycle Proteins / biosynthesis
  • Cell Cycle Proteins / genetics
  • Cell Growth Processes / physiology
  • Cell Nucleus / metabolism
  • Cricetinae
  • Cyclin-Dependent Kinase Inhibitor p21
  • Down-Regulation
  • HSP27 Heat-Shock Proteins
  • HeLa Cells
  • Heat-Shock Proteins / biosynthesis
  • Heat-Shock Proteins / genetics
  • Humans
  • K562 Cells
  • Mice
  • Mice, Nude
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • S100 Calcium-Binding Protein A4
  • S100 Proteins / biosynthesis
  • S100 Proteins / genetics
  • Transfection

Substances

  • Antigens, Neoplasm
  • CDKN1A protein, human
  • Cdkn1a protein, mouse
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • HSP27 Heat-Shock Proteins
  • HSPB1 protein, human
  • Heat-Shock Proteins
  • Neoplasm Proteins
  • PRAME protein, human
  • Recombinant Fusion Proteins
  • S100 Calcium-Binding Protein A4
  • S100 Proteins
  • S100a4 protein, mouse
  • S100A4 protein, human
  • Caspases