Signalling responses linked to betulinic acid‐induced apoptosis are antagonized by MEK inhibitor U0126 in adherent or 3D spheroid melanoma irrespective of p53 status
Open Access
- 20 December 2005
- journal article
- research article
- Published by Wiley in International Journal of Cancer
- Vol. 118 (5), 1135-1143
- https://doi.org/10.1002/ijc.21478
Abstract
MEK1/2 inhibitors like U0126 can potentiate or antagonize the antitumor activity of cytotoxic agents such as cisplatin, paclitaxel or vinblastine, depending on the drug or the target cells. We now investigated whether U0126, differentially regulates melanoma signaling in response to UV radiation or betulinic acid, a drug lethal against melanoma. This report shows that U0126 inhibits early response (ERK) kinase activation and cyclin A expression in wt p53 C8161 melanoma exposed to either UV radiation or betulinic acid. However, U0126 does not protect from UV damage, but counteracts betulinic acid-mediated apoptosis in the same cells. Protection from the latter drug by joint treatment with U0126 was also evident in wt p53 MelJuso melanoma and mutant p53 WM164 melanoma. The latter cells were the most responsive to betulinic acid, showing a selective decline in the cdk4 protein, without a comparable change in other key cell cycle proteins like cdc2, cdk2, cdk7 or cyclin A, prior to apoptosis-associated PARP fragmentation. Laser scanning cytometry also showed that betulinic acid induced a significant increase in chromatin condensation in WM164 melanoma irrespective of whether they were in adherent form or as multicellular spheroids. All these betulinic acid-induced changes were counteracted by U0126. Our data show for the first time that (a) cdk4 protein is an early target of betulinic acid-induced apoptosis and (b) unrestricted ERK signaling favours betulinic acid-induced apoptosis, but this is counteracted by U0126, partly through counteracting chromatin condensation and restoring Akt activation decreased by betulinic acid treatment.Keywords
This publication has 30 references indexed in Scilit:
- Topical Treatment with Inhibitors of the Phosphatidylinositol 3′-Kinase/Akt and Raf/Mitogen-Activated Protein Kinase Kinase/Extracellular Signal-Regulated Kinase Pathways Reduces Melanoma Development in Severe Combined Immunodeficient MiceCancer Research, 2004
- ERK Activation Mediates Cell Cycle Arrest and Apoptosis after DNA Damage Independently of p53Journal of Biological Chemistry, 2002
- Apoptosis and melanogenesis in human melanoma cells induced by anthrax lethal factor inactivation of mitogen-activated protein kinase kinaseProceedings of the National Academy of Sciences, 2002
- U0126, a mitogen-activated protein kinase kinase inhibitor, inhibits the invasion of human A375 melanoma cellsCancer Letters, 2002
- Development of anticancer drugs targeting the MAP kinase pathwayOncogene, 2000
- Requirement for ERK Activation in Cisplatin-induced ApoptosisJournal of Biological Chemistry, 2000
- MEK Inhibition Enhances Paclitaxel-induced Tumor ApoptosisJournal of Biological Chemistry, 2000
- Apoptosis-inducing levels of uv radiation and proteasome inhibitors produce opposite effects on p21WAF1 in human melanoma cellsInternational Journal of Cancer, 2000
- Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivoNature Medicine, 1999
- Inhibition of the Mitogen-activated Protein Kinase Pathway Triggers B16 Melanoma Cell DifferentiationJournal of Biological Chemistry, 1998