Geldanamycin mediates the apoptosis of gastric carcinoma cells through inhibition of EphA2 protein expression.

Abstract

The aim of the present study was to investigate the role of EphA2 in the carcinogenesis and progression of gastric carcinoma. Moreover, we aimed to determine the effect of geldanamycin (GA), an inhibitor of Hsp90, on the proliferation and apoptosis of human gastric carcinoma cells. Gastric carcinoma tissues, paired adjacent mucosa and paired normal mucosa were obtained from resected surgical specimens of gastric carcinoma, and EphA2 mRNA and protein levels were assessed by RT-PCR, immunohistochemistry and western blot analysis. FCM was used to detect cell cycle distribution and apoptosis. MGC803 cell proliferation and apoptosis were assessed by MTT and FCM, respectively. We found that EphA2 protein was increased in the carcinogenesis of gastric epithelial cells. Proliferation index (PI) was significantly upregulated following an increase in EphA2 expression in gastric carcinoma compared with dysplasia and normal samples, and was notably correlated with grade and lymph node metastasis. Knockdown of EphA2 increased the apoptosis rate and decreased the PI of MGC803 cells, which overexpressed the EphA2 protein. GA inhibited the cell proliferation of MGC803 cells in a dose- and time-dependent manner and induced cell apoptosis. In addition, GA decreased the EphA2 protein expression in MGC803 cells. Overexpression of EphA2 inhibited cell growth, blocked cells in the G0/G1 stage and increased cell apoptosis induced by GA in MGC803 cells. However, knockdown of EphA2 in MGC803 cells increased the apoptosis ratio induced by GA. In conclusion, EphA2 overexpression is an important characteristic in the carcinogenesis of gastric epithelial cells, followed by an increase in apoptosis and cell cycle arrest. Knockdown of EphA2 blocked MGC803 cell proliferation and induced cell apoptosis. In conclusion GA inhibits MGC803 cell proliferation and induces cell apoptosis by upregulating expression of EphA2.

• Authors: Da-Hu Wang, Yu-Jun Zhang, San-Bing Zhang, Hui Liu, Liang Liu, Feng-Ling Liu, Jing Zuo
• Journal: Oncology reports (Oncol Rep) Vol. 32 Issue 6 Pg. 2429-36 (Dec 2014) ISSN: 1791-2431 [Electronic] Greece
• PMID: 25310629 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Benzoquinones
• Lactams, Macrocyclic
• Receptor, EphA2
• geldanamycin

Topics

• Antibiotics, Antineoplastic (pharmacology)
• Apoptosis (drug effects)
• Benzoquinones (pharmacology)
• Carcinoma (drug therapy, metabolism, secondary)
• Cell Cycle
• Cell Differentiation
• Cell Line, Tumor
• Cell Proliferation
• Humans
• Lactams, Macrocyclic (pharmacology)
• Lymphatic Metastasis
• Receptor, EphA2 (genetics, metabolism)
• Stomach Neoplasms (drug therapy, metabolism, pathology)