Journal article
Effects of protein kinase C modulation by PEP005, a novel ingenol angelate, on mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling in cancer cells
Molecular Cancer Therapeutics, Vol.7(4), pp.915-922
2008
Abstract
PEP005 (ingenol-3-angelate) is a novel anticancer agent extracted from Euphorbia peplus that was previously shown to modulate protein kinase C (PKC), resulting in antiproliferative and proapoptotic effects in several human cancer cell lines. In Colo205 colon cancer cells, exposure to PEP005 induced a time- and concentration-dependent decrease of cells in S phase of cell cycle and apoptosis. In Colo205 cells exposed to PEP005, a variety of signaling pathways were activated as shown by increased phosphorylation of PKCδ, Raf1, extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase (MAPK), c-Jun NH2-terminal kinase, p38 MAPK, and PTEN. PEP005-induced activation of PKCδ was associated with its translocation from the cytosol to the nucleus and other cellular membranes. Interestingly, PEP005 treatment also resulted in reduced expression of PKCα and reduced levels of phosphorylated active form of AKT/protein kinase B. These data suggest that PEP005-induced activation of PKCδ and reduced expression of PKCα resulted in apoptosis by mechanisms mediated by activation of Ras/Raf/MAPK and inhibition of the phosphatidylinositol 3-kinase/AKT signaling pathways. This study supports ongoing efforts targeting PKC isoforms in cancer therapy with PEP005 alone and in combination with other cytotoxic agents.
Details
- Title
- Effects of protein kinase C modulation by PEP005, a novel ingenol angelate, on mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling in cancer cells
- Authors
- M Serova (Author) - Beaujon University Hospital, FranceA Ghoul (Author) - Beaujon University Hospital, FranceK A Benhadji (Author) - Beaujon University Hospital, FranceS Faivre (Author) - Beaujon University Hospital, FranceC Le Tourneau (Author) - Beaujon University Hospital, FranceE Cvitkovic (Author) - AAI Oncology, Kremlin-Bicetre, FranceF Lokiec (Author) - Rene' Huguenin Cancer Center, FranceJ Lord (Author) - MRC Center for Immune Regulation, Birmingham, United KingdomSteven Ogbourne (Author) - Peplin Ltd.F Calvo (Author) - Saint-Louis Hospital, United KingdomE Raymond (Author) - Beaujon University Hospital, France
- Publication details
- Molecular Cancer Therapeutics, Vol.7(4), pp.915-922
- Publisher
- American Association for Cancer Research
- DOI
- 10.1158/1535-7163.MCT-07-2060
- ISSN
- 1535-7163
- Organisation Unit
- School of Science and Engineering - Legacy; Centre for Bioinnovation; School of Science, Technology and Engineering; University of the Sunshine Coast, Queensland
- Language
- English
- Record Identifier
- 99449800602621
- Output Type
- Journal article
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