A role for p38 MAPK in head and neck cancer cell growth and tumor-induced angiogenesis and lymphangiogenesis.
We have recently gained a remarkable understanding of the mutational landscape of head and neck squamous cell carcinoma (HNSCC). However, the nature of the dysregulated signaling networks contributing to HNSCC progression is still poorly defined. Here, we have focused on the role of the family of mitogen activated kinases (MAPKs), extracellular regulated kinase (ERK), c-Jun terminal kinase (JNK) and p38 MAPK in HNSCC. Immunohistochemical analysis of a large collection of human HNSCC tissues revealed that the levels of the phosphorylated active form of ERK1/2 and JNK were elevated in less than 33% and 16% of the cases, respectively. Strikingly, however, high levels of active phospho-p38 were observed in most (79%) of hundreds of tissues analyzed. We explored the biological role of p38 in HNSCC cell lines using three independent approaches: treatment with a specific p38 inhibitor, SB203580; a retro-inhibition strategy consisting in the use of SB203580 combined with the expression of an inhibitor-insensitive mutant form of p38α; and short-hairpin RNAs (shRNAs) targeting p38α. We found that specific blockade of p38 signaling significantly inhibited the proliferation of HNSCC cells both in vitro and in vivo. Indeed, we observed that p38 inhibition in HNSCC cancer cells reduces cancer growth in tumor xenografts and a remarkable decrease in intratumoral blood and lymphatic vessels. We conclude that p38α functions as a positive regulator of HNSCC in the context of the tumor microenvironment, controlling cancer cell growth as well as tumor-induced angiogenesis and lymphangiogenesis.
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA; Faculty of Dentistry, Thammasat University, Pathumthani, Thailand.
Kantima
K
Leelahavanichkul
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA.
Panomwat
P
Amornphimoltham
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA.
Alfredo A
AA
Molinolo
Department of Oncology and Diagnostic Sciences, Dental School, University of Maryland, Baltimore, MD, USA.
John R
JR
Basile
Faculty of Dentistry, Thammasat University, Pathumthani, Thailand.
Sittichai
S
Koontongkaew
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA. Electronic address: sg39v@nih.gov.
J Silvio
JS
Gutkind
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016207:Cytokines / Q000032:analysis; D004789:Enzyme Activation; D005260:Female; D006258:Head and Neck Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D042583:Lymphangiogenesis; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000473:pathology; D000077195:Squamous Cell Carcinoma of Head and Neck; D059016:Tumor Microenvironment; D048051:p38 Mitogen-Activated Protein Kinases / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*
D016207:Cytokines; D048051:p38 Mitogen-Activated Protein Kinases
Angiogenesis; Head and neck cancer; JNK; Lymphangiogenesis; MAPK; p38 Inhibitor; p38 MAPK