p53-Mediated enhancement of radiosensitivity by selenophosphate synthetase 1 overexpression

J Cell Physiol. 2006 Oct;209(1):131-41. doi: 10.1002/jcp.20714.

Abstract

Selenium has been associated with cancer prevention. Despite vast knowledge of selenium effect on various health conditions, functional characterization of selenium metabolic enzymes on cellular physiology has been limited. Therefore, to gain insight into the mechanisms underlying cancer prevention by selenium, we investigated sps1, one of the two human selenophosphate synthetase genes for its role in cancer cell's response to ionizing radiation. Although stable expression of Sps1 protein per se had little effect on cell proliferation, concurrent irradiation decreased viability of the sps1 cell line. The increased sensitivity of the cell lines to ionizing radiation was correlated with increased p53 activity as well as with simultaneous up- and downregulation of Bax and Bcl2, respectively. Knockdown of sps1 and p53 by small interfering RNA method revealed that the level of p53 was proportional to that of Sps1 and that the increased radiosensitivity was dependent upon p53. Sps1 cell lines displayed decreased level of reactive oxygen species (ROS) with concomitant increase of certain redox enzymes. Furthermore, p53 activity was regulated by cellular redox via Ref1 in sps1 cell lines. Collectively, our results demonstrated that sps1 was able to affect cell viability upon ionizing radiation via modulation of p53 activity. They further suggest that Sps1 and its reaction product selenophosphate might be involved in cancer prevention in a p53-dependent manner and could be applied to development of a novel cancer therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • DNA-Binding Proteins / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Activation
  • Humans
  • Phosphotransferases / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism
  • Radiation Tolerance*
  • Sodium Selenite / pharmacology
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Protein p53 / physiology*
  • Tumor Suppressor Proteins / metabolism

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Phosphotransferases
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein-Serine-Threonine Kinases
  • selenophosphate synthetase
  • Sodium Selenite