title: Loss of p38δ mitogen-activated protein kinase expression promotes oesophageal squamous cell carcinoma proliferation, migration and anchorage-independent growth.
abstract: Oesophageal cancer is an aggressive tumour which responds poorly to both chemotherapy and radiation therapy and has a poor prognosis. Thus, a greater understanding of the biology of oesophageal cancer is needed in order to identify novel therapeutic targets. Among these targets p38 MAPK isoforms are becoming increasingly important for a variety of cellular functions. The physiological functions of p38α and -β are now well documented in contrast to -γ and -δ which are comparatively under-studied and ill-defined. A major obstacle to deciphering the role(s) of the latter two p38 isoforms is the lack of specific chemical activators and inhibitors. In this study, we analysed p38 MAPK isoform expression in oesophageal cancer cell lines as well as human normal and tumour tissue. We observed specifically differential p38δ expression. The role(s) of p38δ and active (phosphorylated) p38δ (p-p38δ) in oesophageal squamous cell carcinoma (OESCC) was delineated using wild-type p38δ as well as active p-p38δ, generated by fusing p38δ to its upstream activator MKK6b(E) via a decapeptide (Gly-Glu)5 linker. OESCC cell lines which are p38δ-negative (KE-3 and -8) grew more quickly than cell lines (KE-6 and -10) which express endogenous p38δ. Re-introduction of p38δ resulted in a time-dependent decrease in OESCC cell proliferation which was exacerbated with p-p38δ. In addition, we observed that p38δ and p-p38δ negatively regulated OESCC cell migration in vitro. Finally both p38δ and p-p38δ altered OESCC anchorage-independent growth. Our results suggest that p38δ and p-p38δ have a role in the suppression of OESCC. Our research may provide a new potential target for the treatment of oesophageal cancer.
authors.affiliation: Department of Pharmacology and Therapeutics, University College Cork, Ireland.
authors.forename: Carol
authors.initials: C
authors.lastname: O'Callaghan
authors.forename: Liam J
authors.initials: LJ
authors.lastname: Fanning
authors.forename: Aileen
authors.initials: A
authors.lastname: Houston
authors.forename: Orla P
authors.initials: OP
authors.lastname: Barry
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D004938:Esophageal Neoplasms / Q000235:genetics / Q000473:pathology*; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D006801:Humans; D048669:MAP Kinase Kinase 6 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D048290:Mitogen-Activated Protein Kinase 11 / Q000096:biosynthesis / Q000378:metabolism; D048291:Mitogen-Activated Protein Kinase 12 / Q000096:biosynthesis / Q000378:metabolism; D048292:Mitogen-Activated Protein Kinase 13 / Q000235:genetics*; D048308:Mitogen-Activated Protein Kinase 14 / Q000096:biosynthesis / Q000378:metabolism; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering
chemical_list: D020033:Protein Isoforms; D034741:RNA, Small Interfering; D048291:Mitogen-Activated Protein Kinase 12; D048292:Mitogen-Activated Protein Kinase 13; D048290:Mitogen-Activated Protein Kinase 11; D048308:Mitogen-Activated Protein Kinase 14; D048669:MAP Kinase Kinase 6