Details

Autor(en) / Beteiligte

• Ng, Hoi Yan
• Ko, Josephine Mun‐Yee
• Yu, Valen Zhuoyou
• Ip, Joseph Chok Yan
• Dai, Wei
• Cal, Santiago
• Lung, Maria Li

Titel

DESC1, a novel tumor suppressor, sensitizes cells to apoptosis by downregulating the EGFR/AKT pathway in esophageal squamous cell carcinoma

Ist Teil von

• International journal of cancer, 2016-06, Vol.138 (12), p.2940-2951

Ort / Verlag

United States: Wiley Subscription Services, Inc

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. What's new? What drives esophageal cancer? These authors combed through cDNA microarrays and found that esophageal squamous cell carcinoma contains lower level of the tumor suppressor DESC1. They then investigated the molecular activity of the DESC1 protein. Under favorable conditions, the cells grew normally, but the presence of DESC1 sensitized cells to conditions that induce apoptosis. That is, the cells without DESC1 withstood the apoptotic stresses, while those expressing DESC1 perished. The location of DESC1 in the cell membrane allows it to interact with the extracellular environment, and they showed that it thus hinders cell colony formation.