Phorbol esters induce death in MCF-7 breast cancer cells with altered expression of protein kinase C isoforms: Role for p53-independent induction of gadd45 in initiating death

James E. De Vente, Cynthia A. Kukoly, Winifred O. Bryant, Karla J. Posekany, Jianming Chen, Donald J. Fletcher, Peter J. Parker, George Pettit, Guillermina Lozano, Paul P. Cook, D. Kirk Ways

Research output: Contribution to journalArticle

64 Scopus citations

Abstract

Protein kinase C (PKC) modulates growth, differentiation, and apoptosis in a cell-specific fashion. Overexpression of PKC-α in MCF-7 breast cancer cells (MCF-7-PKC-α cell) leads to expression of a more transformed phenotype. The response of MCF-7 and MCF-7-PKC-α cells to phorbol esters (TPA) was examined. TPA-treated MCF-7 cells demonstrated a modest cytostatic response associated with a G1 arrest that was accompanied by Cip1 expression and retinoblastoma hypophosphorylation. While p53 was detected in MCF-7 cells, evidence for TPA-induced stimulation of p53 transcriptional activity was not evident. In contrast, TPA treatment induced death of MCF-7-PKC-α cells. Bryostatin 1, another PKC activator, exerted modest cytostatic effects on MCF-7 cells while producing a cytotoxic response at low doses in MCF-7-PKC-α cells that waned at higher concentrations. TPA-treated MCF-7-PKC-α cells accumulated in G2/M, did not express p53, displayed decreased Cip1 expression, and demonstrated a reduction in retinoblastoma hypophosphorylation. TPA-treated MCF-7-PKC-α cells expressed gadd45 which occurred before the onset of apoptosis. Thus, alterations in the PKC pathway can modulate the decision of a breast cancer cell to undergo death or differentiation. In addition, these data show that PKC activation can induce expression of gadd45 in a p53-independent fashion.

Original languageEnglish (US)
Pages (from-to)1874-1886
Number of pages13
JournalJournal of Clinical Investigation
Volume96
Issue number4
DOIs
StatePublished - Oct 1995

Keywords

  • Apoptosis
  • Breast cancer
  • Phorbol esters
  • Protein kinase C
  • p53

ASJC Scopus subject areas

  • Medicine(all)

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    De Vente, J. E., Kukoly, C. A., Bryant, W. O., Posekany, K. J., Chen, J., Fletcher, D. J., Parker, P. J., Pettit, G., Lozano, G., Cook, P. P., & Ways, D. K. (1995). Phorbol esters induce death in MCF-7 breast cancer cells with altered expression of protein kinase C isoforms: Role for p53-independent induction of gadd45 in initiating death. Journal of Clinical Investigation, 96(4), 1874-1886. https://doi.org/10.1172/JCI118233