Inhibition of p38 MAPK enhances ABT‐737‐induced cell death in melanoma cell lines: novel regulation of PUMA
Identifieur interne : 001710 ( Main/Exploration ); précédent : 001709; suivant : 001711Inhibition of p38 MAPK enhances ABT‐737‐induced cell death in melanoma cell lines: novel regulation of PUMA
Auteurs : Angela M. Keuling [Canada] ; Susan E. Andrew [Canada] ; Victor A. Tron [Canada]Source :
- Pigment Cell & Melanoma Research [ 1755-1471 ] ; 2010-06.
English descriptors
- Teeft :
- Ammonium chloride, Apoptosis, Apoptotic, Apoptotic cell death, Assay, Caspase, Caspase cleavage, Cell death, Cell lines, Cell survival, Cleavage, Combination treatment, Combination treatments, Cutaneous melanoma, Dos, Dsirna, Dsirna combination, Enantiomer, Enantiomer control, Family members, Family proteins, Future studies, Imvi, Imvi cells, Inhibition, Inhibitor, John wiley sons, Keuling, Knockdown, Malignant melanoma, Mapk, Melanoma, Melanoma cell lines, Melanoma cells, Metastatic melanoma, Pathway, Proteasome, Proteasome inhibitors, Protein puma, Puma, Puma knockdown, Puma levels, Single treatment, Sirna, Supplementary figure, Synergistic effect, Treatment response, Triple combination, Viability, Western immunoblots.
Abstract
The mitogen‐activated protein kinase (MAPK) pathway is constitutively activated in the majority of melanomas, promoting cell survival, proliferation and migration. In addition, anti‐apoptotic Bcl‐2 family proteins Mcl‐1, Bcl‐xL and Bcl‐2 are frequently overexpressed, contributing to melanoma’s well‐documented chemoresistance. Recently, it was reported that the combination of MAPK pathway inhibition by specific MEK inhibitors and Bcl‐2 family inhibition by BH3‐mimetic ABT‐737 synergistically induces apoptotic cell death in melanoma cell lines. Here we provide the first evidence that inhibition of another key MAPK, p38, synergistically induces apoptosis in melanoma cells in combination with ABT‐737. We also provide novel mechanistic data demonstrating that inhibition of p38 increases expression of pro‐apoptotic Bcl‐2 protein PUMA. Furthermore, we demonstrate that PUMA can be cleaved by a caspase‐dependent mechanism during apoptosis and identify what appears to be the PUMA cleavage product. Thus, our findings suggest that the combination of ABT‐737 and inhibition of p38 is a promising, new treatment strategy that acts through a novel PUMA‐dependent mechanism.
Url:
DOI: 10.1111/j.1755-148X.2010.00698.x
Affiliations:
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