title: DESC1, a novel tumor suppressor, sensitizes cells to apoptosis by downregulating the EGFR/AKT pathway in esophageal squamous cell carcinoma.
abstract: Esophageal cancer is ranked as the eighth most common cancer and the sixth leading cause of cancer deaths worldwide. To identify candidate tumor suppressor genes related to esophageal squamous cell carcinoma (ESCC) development, a cDNA microarray analysis was performed using paired tumor and nontumor tissue samples from ESCC patients. Differentially expressed in squamous cell carcinoma 1 (DESC1), which belongs to the Type II transmembrane serine protease family, was frequently downregulated in ESCC. This study aims to elucidate the molecular mechanism for the tumor suppressive function of DESC1 in ESCC. We show that DESC1 reduced cell viability and sensitized cells to apoptosis, when cells were under apoptotic stimuli. The proapoptotic effect of DESC1 was mediated through downregulating AKT1 activation and the restoration of AKT activation by the introduction of the constitutively active AKT, myr-AKT, abolished the apoptosis-sensitizing effect of DESC1. DESC1 also reduced EGFR protein level, which was abrogated when the proteolytic function of DESC1 was lost, suggesting that DESC1 cleaved EGFR and downregulated the EGFR/AKT pathway to favor apoptosis. The transmembrane localization and the structural domains provide an opportunity for DESC1 to interact with the extracellular environment. The importance of such interaction was highlighted by the finding that DESC1 reduced cell colony formation ability in three-dimensional culture. In line with this, DESC1 reduced tumor growth kinetics in the in vivo orthotopic tumorigenesis assay. Taken together, our novel findings suggest how DESC1 may suppress ESCC development by sensitizing cells to apoptosis under an apoptotic stimulus through downregulating the EGFR/AKT signaling pathway.
authors: Department of Clinical Oncology, Faculty of Medicine, University of Hong Kong Li Ka Shing, Pokfulam, Hong Kong, SAR.
authors: Hoi Yan
authors: HY
authors: Ng
authors: Department of Clinical Oncology, Faculty of Medicine, University of Hong Kong Li Ka Shing, Pokfulam, Hong Kong, SAR.
authors: Josephine Mun-Yee
authors: JM
authors: Ko
authors: Department of Clinical Oncology, Faculty of Medicine, University of Hong Kong Li Ka Shing, Pokfulam, Hong Kong, SAR.
authors: Valen Zhuoyou
authors: VZ
authors: Yu
authors: Department of Clinical Oncology, Faculty of Medicine, University of Hong Kong Li Ka Shing, Pokfulam, Hong Kong, SAR.
authors: Joseph Chok Yan
authors: JC
authors: Ip
authors: Department of Clinical Oncology, Faculty of Medicine, University of Hong Kong Li Ka Shing, Pokfulam, Hong Kong, SAR.
authors: Wei
authors: W
authors: Dai
authors: Departamento De Bioquímica Y Biología Molecular, Instituto Universitario De Oncología, Universidad De Oviedo, Spain.
authors: Santiago
authors: S
authors: Cal
authors: Department of Clinical Oncology, Faculty of Medicine, University of Hong Kong Li Ka Shing, Pokfulam, Hong Kong, SAR.
authors: Maria Li
authors: ML
authors: Lung
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000201:enzymology*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000378:metabolism*; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000964:Antimetabolites, Antineoplastic; D008565:Membrane Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D012697:Serine Endopeptidases; C524420:TMPRSS11E protein, human; D005472:Fluorouracil
keywords: apoptosis; differentially expressed in squamous cell carcinoma 1; esophageal squamous cell carcinoma; transmembrane serine protease