Induction of Senescence in Diterpene Ester–Treated Melanoma Cells via Protein Kinase C–Dependent Hyperactivation of the Mitogen-Activated Protein Kinase Pathway

S J Cozzi; P Parsons; Steven Ogbourne; J Pedley; G M Boyle

doi:10.1158/0008-5472.CAN-06-0348

Back

Induction of Senescence in Diterpene Ester–Treated Melanoma Cells via Protein Kinase C–Dependent Hyperactivation of the Mitogen-Activated Protein Kinase Pathway

Journal article

Peer reviewed

Induction of Senescence in Diterpene Ester–Treated Melanoma Cells via Protein Kinase C–Dependent Hyperactivation of the Mitogen-Activated Protein Kinase Pathway

S J Cozzi, P Parsons, Steven Ogbourne, J Pedley and G M Boyle

Cancer Research, Vol.66(20), pp.10083-10091

2006

DOI: https://doi.org/10.1158/0008-5472.CAN-06-0348

Files and links (1)

url

https://doi.org/10.1158/0008-5472.CAN-06-0348View

Published Version

Abstract

Oncology and Carcinogenesis

senescence

PEP005

PMA

PKC

MAPK pathway

The diterpene ester PEP005 is a novel anticancer agent that activates protein kinase C (PKC) and induces cell death in melanoma at high doses. We now describe the in vitro cytostatic effects of PEP005 and the diterpene ester phorbol 12-myristate 13-acetate, observed in 20% of human melanoma cell lines. Primary cultures of normal human neonatal fibroblasts were resistant to growth arrest, indicating a potential for tumor selectivity. Sensitive cell lines were induced to senesce and exhibited a G1 and G2-M arrest. There was sustained expression of p21WAF1/CIP1, irreversible dephosphorylation of the retinoblastoma protein, and transcriptional silencing of E2F-responsive genes in sensitive cell lines. Activation of mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK) 1/2 by PKC was required for diterpene ester-induced senescence. Expression profiling revealed that the MAP kinase inhibitor HREV107 was expressed at a higher transcript level in resistant compared with sensitive cell lines. We propose that activation of PKC overstimulates the RAS/RAF/MEK/ERK pathway, resulting in molecular changes leading to the senescent phenotype. (Cancer Res 2006; 66(20): 10083-91)

Details

Title: Induction of Senescence in Diterpene Ester–Treated Melanoma Cells via Protein Kinase C–Dependent Hyperactivation of the Mitogen-Activated Protein Kinase Pathway
Authors: S J Cozzi (Author) - Queensland Institute of Medical Research
P Parsons (Author) - Queensland Institute of Medical Research
Steven Ogbourne (Author) - Queensland Institute of Medical Research
J Pedley (Author) - Queensland Institute of Medical Research
G M Boyle (Author) - Queensland Institute of Medical Research
Publication details: Cancer Research, Vol.66(20), pp.10083-10091
Publisher: American Association for Cancer Research
Date published: 2006
DOI: 10.1158/0008-5472.CAN-06-0348
ISSN: 0008-5472
Organisation Unit: School of Science and Engineering - Legacy; University of the Sunshine Coast, Queensland; School of Science, Technology and Engineering; Centre for Bioinnovation
Language: English
Record Identifier: 99449614002621
Output Type: Journal article

Metrics

508 Record Views

51 Times Cited - Web of Science

InCites Highlights

These are selected metrics from InCites Benchmarking & Analytics tool, related to this output

Collaboration types: Domestic collaboration
Web Of Science research areas: Oncology

UN Sustainable Development Goals (SDGs)

This output has contributed to the advancement of the following goals:

Source: InCites