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p38 alpha and p38 delta mitogen-activated protein kinase isoforms regulate invasion and growth of head and neck squamous carcinoma cells
- Source :
- Oncogene. 26(36):5267-5279
- Publication Year :
- 2007
-
Abstract
- Recent studies indicate that the specificity of p38 mitogen-activated protein kinase (MAPK)-mediated cellular stress responses is determined by the expression pattern of the distinct p38 isoforms. Here, we have analysed the function of distinct p38 isoforms in the growth and invasion of head and neck squamous cell carcinomas (HNSCCs). Activation of p38 MAPK by arsenite resulted in inactivation of the ERK1,2 signaling pathway by dephosphorylation of MEK1,2 in primary human epidermal keratinocytes (HEKs), whereas in HNSCC cells this p38-mediated inhibition of the ERK1,2 pathway was absent. Quantitation of p38 pathway component mRNA expression in HNSCC cell lines (n=42) compared to HEKs (n=8) revealed that p38alpha and p38delta isoforms are predominantly expressed in both cell types and that MKK3 is the primary upstream activator expressed. Inhibition of endogenous p38alpha or p38delta activity by adenoviral delivery of corresponding dominant-negative p38 isoforms potently reduced MMP-13 and MMP-1 expressions, and suppressed the invasion of HNSCC cells through collagen. Dominant-negative p38alpha and p38delta inhibited squamous cell carcinoma (SCC) cell proliferation and inhibition of p38alpha activity also compromised survival of SCC cells. p38alpha and p38delta were predominantly expressed in HNSCCs (n=24) and nonneoplastic epithelium in vivo (n=6), with MKK3 being the primary upstream activator. Activation and expression of p38alpha and p38delta by tumor cells was detected in HNSCCs in vivo (n=16). Adenoviral expression of dominant-negative p38alpha or p38delta in cutaneous SCC cells potently inhibited their implantation in skin of severe combined immunodeficiency mice and growth of xenografts in vivo. Our results indicate that p38alpha and p38delta specifically promote the malignant phenotype of SCC cells by regulating cell survival, proliferation and invasion, suggesting these p38 MAPK isoforms as potential therapeutic targets in HNSCCs.
- Subjects :
- MAPK/ERK pathway
Keratinocytes
Cancer Research
Cell type
Cell
Blotting, Western
Biology
ta3111
p38 Mitogen-Activated Protein Kinases
Cell Line, Tumor
Genetics
medicine
Humans
Neoplasm Invasiveness
Molecular Biology
DNA Primers
Base Sequence
Cell growth
ta1182
ta3121
medicine.disease
Flow Cytometry
ta3122
Head and neck squamous-cell carcinoma
Immunohistochemistry
Matrix Metalloproteinases
Squamous carcinoma
Enzyme Activation
Isoenzymes
medicine.anatomical_structure
Epidermoid carcinoma
Cell culture
Head and Neck Neoplasms
Immunology
Cancer research
Carcinoma, Squamous Cell
Cell Division
Signal Transduction
Subjects
Details
- ISSN :
- 09509232
- Volume :
- 26
- Issue :
- 36
- Database :
- OpenAIRE
- Journal :
- Oncogene
- Accession number :
- edsair.doi.dedup.....07a48b91b5873396b5eae2a331384f6d