IFN-γ regulation of vacuolar pH, cathepsin D processing and autophagy in mammary epithelial cells

Zhila Khalkhali-Ellis*, Daniel E. Abbott, Caleb M. Bailey, William Goossens, Naira V. Margaryan, Stephen L. Gluck, Moshe Reuveni, Mary J.C. Hendrix

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

In this study we examined the ability of interferon-γ (IFN-γ) to regulate mammary epithelial cell growth and gene expression, with particular emphasis on two genes: Maspin (a member of serine protease inhibitor superfamily), and the lysosomal aspartyl endopeptidase cathepsin D (CatD). The protein products of these genes are critically involved in regulation of multitude of biological functions in different stages of mammary tissue development and remodeling. In addition, the expression of Maspin is down-regulated in primary breast cancer and is lost in metastatic disease, while CatD is excessively produced and aberrantly secreted by breast cancer cells. We report that IFN-γ receptors are expressed in mammary epithelial cells, and receptor engagement by IFN-γ transduces the IFN-γ signal via Stat-1 resulting in decreased vacuolar pH. This change in vacuolar pH alters CatD protein processing and secretion concurrent with increased Maspin secretion. In addition, IFN-γ exerts a suppressive effect on cell growth and proliferation, and induces morphological changes in mammary epithelial cells. Our studies also reveal that breast cancer cells, which are devoid of Maspin, are refractory to IFN-γ with respect to changes in vacuolar pH and CatD. However, Maspin transfection of breast cancer cells partially sensitizes the cells to IFN-γ's effect, thus providing new therapeutic implications.

Original languageEnglish (US)
Pages (from-to)208-218
Number of pages11
JournalJournal of Cellular Biochemistry
Volume105
Issue number1
DOIs
StatePublished - Sep 1 2008

Keywords

  • Autophagy
  • Breast cancer
  • Cathepsin D
  • IFN-γ
  • Mammary epithelial cell
  • Maspin
  • vATPase

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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