Stimulation of protein kinase C-dependent and -independent signaling pathways by bistratene A in intestinal epithelial cells

Mark R. Frey, Olga Leontieva, Dianne J. Watters, Jennifer D. Black

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


The marine toxin bistratene A (BisA) potently induces cytostasis and differentiation in a variety of systems. Evidence that BisA is a selective activator of protein kinase C (PKC) δ implicates PKC δ signaling in the negative growth-regulatory effects of this agent. The current study further investigates the signaling pathways activated by BisA by comparing its effects with those of the PKC agonist phorbol 12-myristate 13-acetate (PMA) in the IEC-18 intestinal crypt cell line. Both BisA and PMA induced cell cycle arrest in these cells, albeit with different kinetics. While BisA produced sustained cell cycle arrest in G0/G1 and G2/M, the effects of PMA were transient and involved mainly a G0/G1 blockade. BisA also produced apoptosis in a proportion of the population, an effect not seen with PMA. Both agents induced membrane translocation/activation of PKC, with BisA translocating only PKC δ and PMA translocating PKC α, δ, and ε in these cells. Notably, while depletion of PKC α, δ, and ε abrogated the cell cycle-specific effects of PMA in IEC-18 cells, the absence of these PKC isozymes failed to inhibit BisA-induced G0/G1 and G2/M arrest or apoptosis. The cell cycle inhibitory and apoptotic effects of BisA, therefore, appear to be PKC-independent in IEC-18 cells. On the other hand, BisA and PMA both promoted PKC-dependent activation of Erk 1 and 2 in this system. Thus, intestinal epithelial cells respond to BisA through activation of at least two signaling pathways: a PKC δ-dependent pathway, which leads to activation of mitogen-activated protein kinase and possibly cytostasis in the appropriate context, and a PKC-independent pathway, which induces both cell cycle arrest in G0/G1 and G2/M and apoptosis through as yet unknown mechanisms.

Original languageEnglish (US)
Pages (from-to)1093-1100
Number of pages8
JournalBiochemical Pharmacology
Issue number9
StatePublished - May 1 2001
Externally publishedYes


  • Bistratene A
  • Cell cycle
  • Intestinal epithelial cells
  • Mitogen-activated protein kinase
  • Protein kinase C
  • Signal transduction

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology


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