Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide

Med Oncol. 2011 Dec;28(4):1225-54. doi: 10.1007/s12032-010-9552-x. Epub 2010 May 11.

Abstract

Arsenic trioxide (As2O3), a component of traditional Chinese medicine, has been used successfully for the treatment of acute promyelocytic leukemia (APL), and As2O3 is of potential therapeutic value for the treatment of other promyelocytic malignancies and some solid tumors including breast cancer. However, the precise molecular mechanisms through which As2O3 induces cell cycle arrest and apoptosis in solid tumors have not been clearly understood. The goal of our study is to gain insight into the general biological processes and molecular functions that are altered by As2O3 treatment in MCF-7 breast cancer cells and to identify the key signaling processes that are involved in the regulation of these physiological effects. In the present study, MCF-7 cells were treated with 5 μM As2O3, and the differential gene expression was then analyzed by DNA microarray. The results showed that As2O3 treatment changed the expression level of several genes that involved in cell cycle regulation, signal transduction, and apoptosis. Notably, As2O3 treatment increased the mRNA and protein levels of the cell cycle inhibitory proteins, p21 and p27. Interestingly, knocking down p21 or p27 individually did not alter As2O3-induced apoptosis and cell cycle arrest; however, the simultaneous down-regulation of both p21 and p27 resulted in attenuating of G1, G2/M arrest and reduction in apoptosis, thus indicating that p21 and p27 as the primary molecular targets of As2O3 against breast cancer. Overall, our results provide new insights into As2O3-related signaling activities, which may facilitate the development of As2O3-based anticancer strategies and/or combination therapies against solid tumors.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / genetics
  • Arsenic Trioxide
  • Arsenicals / pharmacology*
  • Blotting, Western
  • Breast Neoplasms / genetics*
  • Cell Line, Tumor
  • Cell Separation
  • Cyclin-Dependent Kinase Inhibitor p21 / biosynthesis
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics*
  • Cyclin-Dependent Kinase Inhibitor p27 / biosynthesis
  • Cyclin-Dependent Kinase Inhibitor p27 / genetics*
  • Female
  • Flow Cytometry
  • Gene Expression / drug effects*
  • Genes, cdc
  • Humans
  • In Situ Nick-End Labeling
  • Oligonucleotide Array Sequence Analysis
  • Oxides / pharmacology*
  • RNA, Small Interfering
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transfection

Substances

  • Antineoplastic Agents
  • Arsenicals
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Oxides
  • RNA, Small Interfering
  • Cyclin-Dependent Kinase Inhibitor p27
  • Arsenic Trioxide