Cell cycle- and protein kinase C-specific effects of resiniferatoxin and resiniferonol 9,13,14-ortho-phenylacetate in intestinal epithelial cells

Mark R. Frey, Jennifer A. Clark, Nicholas W. Bateman, Marcelo G. Kazanietz, Adrian R. Black, Jennifer D. Black*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


We have previously reported that protein kinase C (PKC) signaling can trigger hallmark events of cell cycle withdrawal in intestinal epithelial cells, including downregulation of cyclin D1, induction of p21Waf1/Cip1, and activation of the growth suppressor function of pocket proteins. In the current study, we compared the cell cycle- and PKC-specific effects of the vanilloid resiniferatoxin (RTX), its parent diterpene resiniferonol 9,13,14-ortho-phenylacetate (ROPA), and the PKC agonist PMA in the IEC-18 non-transformed intestinal crypt cell line. ROPA and PMA were found to produce strikingly similar alterations in cell cycle progression and PKC activity in IEC-18 cells, although PMA was approximately 1000-fold more potent in producing these effects. Both agents induced a transient PKC-dependent blockade in G 1→S progression associated with transient downregulation of cyclin D1 and induction of p21Waf1/Cip1. In contrast, RTX produced a prolonged PKC-independent cell cycle arrest in G0/G1 phase which was maintained for longer than 24 h. This arrest was vanilloid receptor-independent and associated with prolonged downregulation of cyclin D1 mRNA and protein, with little effect on levels of p21Waf1/Cip1. Combined exposure to RTX and ROPA produced a sustained and complete cell cycle blockade in IEC-18 cells, associated with depletion of cyclin D1 and sustained enhancement of p21Waf1/Cip1 levels. PMA, ROPA, RTX and the RTX/ROPA combination were capable of activating ERK1/2 signaling in IEC-18 cells, albeit with different kinetics. In contrast, only PMA and ROPA activated JNK1/2 and p38 in this system. Notably, some preparations of commercially obtained RTX produced effects indistinguishable from those of the RTX/ROPA combination, suggesting that certain batches of the compound may contain significant amounts of ROPA (or another PKC agonist activity). Together, these data demonstrate that structurally related compounds can produce similar cell cycle-specific effects but through distinct mechanisms. In addition, they add to a growing body of evidence that vanilloids can have antiproliferative effects in a variety of cell types.

Original languageEnglish
Pages (from-to)1873-1886
Number of pages14
JournalBiochemical Pharmacology
Issue number10
StatePublished - 15 May 2004
Externally publishedYes


  • BIM I
  • Cell cycle
  • PDBu
  • PKC
  • PMA
  • Protein kinase C
  • ROPA
  • RTX
  • Resiniferatoxin
  • bisindolylmaleimide I
  • phorbol 12,13-dibutyrate
  • phorbol 12-myristate 13-acetate
  • protein kinase C
  • resiniferatoxin
  • resiniferonol 9,13,14-ortho-phenylacetate


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