Conjugated linoleic acids (CLAs) regulate the expression of key apoptotic genes in human breast cancer cells

FASEB J. 2002 Sep;16(11):1447-9. doi: 10.1096/fj.01-0720fje. Epub 2002 Jul 18.

Abstract

Conjugated linoleic acid (CLA) reduces mammary tumorigenesis in rodent models, induces apoptosis in rodent mammary tumor cell lines, and decreases expression of antiapoptotic bcl-2 in rat mammary tissue. This investigation focused on the cell mechanisms underlying the antitumor effects of CLA. Changes (mRNA, protein) in expression of major proapoptotic p53, p21WAF1/CIP1, bax, bcl-Xs genes, and the antiapoptotic bcl-2 gene were observed in malignant MCF-7 and MDA-MB-231 cells and in benign MCF-10a human mammary tumor cells in culture. CLA, but not linoleic acid (LA), inhibited proliferation in all cells; CLA mix was most effective. CLA increased DNA damage (apoptosis). CLA increased mRNA expression of p53 and p21WAF1/CIP1 (three- to fivefold and twofold, respectively) but either decreased bcl-2 by 20-30% or had no effect in MCF-7 and MCF-10a cells, respectively; protein expression reflected mRNA values. In MDA-MBA-231 (mutant p53) cells, mRNA for p53 was not changed, but p21WAF1/CIP1 and bcl-2 mRNA was increased. Protein expression largely reflected mRNA changes but, surprisingly, CLA completely suppressed mutant p53 protein in MDA-MB-231 cells. Apparent antiapoptotic effects of increased bcl-2 expression in MDA-MBA-231 cells were countered by increased proapoptotic p21WAF1/CIP1, Bax, and Bcl-Xs proteins. Findings indicate that CLA elicits mainly proapoptotic effects in human breast tumor cells through both p53-dependent and p53-independent pathways, according to cell type.

MeSH terms

  • Apoptosis*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / biosynthesis
  • Cyclins / genetics
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Linoleic Acids / pharmacology*
  • Models, Biological
  • Mutation
  • Proto-Oncogene Proteins / biosynthesis*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • RNA, Neoplasm / biosynthesis
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / biosynthesis
  • Tumor Suppressor Protein p53 / genetics
  • bcl-2-Associated X Protein
  • bcl-X Protein

Substances

  • BAX protein, human
  • BCL2L1 protein, human
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Linoleic Acids
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Neoplasm
  • Tumor Suppressor Protein p53
  • bcl-2-Associated X Protein
  • bcl-X Protein