HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: M800195-MCP200v1 8/1/70    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Glossary Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Liu, R. Articles by Huang, C. Search for Related Content PubMed PubMed Citation Articles by Liu, R. Articles by Huang, C. Social Bookmarking                      What's this?

Molecular & Cellular Proteomics 8:70-85, 2009.
© 2009 by The American Society for Biochemistry and Molecular Biology, Inc.

---

Research

Mechanism of Cancer Cell Adaptation to Metabolic Stress

Proteomics Identification of a Novel Thyroid Hormone-mediated Gastric Carcinogenic Signaling Pathway^*

Rui Liu^,, Zhenjun Li^,, Shujun Bai^,, Haiyuan Zhang^¶, Minghai Tang, Yunlong Lei, Lijuan Chen, Shufang Liang, Ying-lan Zhao, Yuquan Wei and Canhua Huang^,||

From the The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China and ^¶ The School of Medicine, Yangtze University, Shashi, Hubei 434000, China

Gastric cancer is the second most common cancer worldwide and has a poor prognosis. To determine the mechanism of adaptation to metabolic stress in cancer cells, we used gastric cancer as a model system to reveal the potential signaling pathways involved. Two-dimensional polyacrylamide gel electrophoresis coupled with ESI-Q-TOF MS/MS analysis was used to identify differentially expressed proteins between gastric tumor tissues and the corresponding noncancerous tissues. In total, 107 spots with significant alteration (±over 2-fold, p < 0.05) were positively identified by MS/MS analysis. Altered expression of representative proteins was validated by RT-PCR and Western blotting. Cluster analysis of the changed proteins revealed an interesting group of metabolic proteins, which suggested accumulation of triiodothyronine (T₃; the major functional component of thyroid hormone) and overexpression of hypoxia-induced factor (HIF) in gastric carcinoma. These observations were further confirmed by electrochemiluminescence immunoassay and immunohistochemistry. T₃-induced expression of HIF1- and vascular endothelial growth factor was further verified using a gastric cancer cell line and in vivo mouse model. Because the early accumulation of HIF1- was found to be independent of de novo transcription, we also found that the cytosolic cascade phosphatidylinositol 3-kinase/Akt pathway sensitive to T₃ stimulus was involved. Furthermore we demonstrated that T₃-induced overexpression of HIF1- was mediated by fumarate accumulation and could be enhanced by fumarate hydratase inactivation but inhibited by 2-oxoglutarate. These results provide evidence for alteration of metabolic proteins and dysfunction of thyroid hormone regulation in gastric tumors, and a novel thyroid hormone-mediated tumorigenic signaling pathway is proposed. Our findings are considered a significant step toward a better understanding of adaptations to metabolic stress in gastric carcinogenesis.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				M. Bhargava, J. Lei, and D. H. Ingbar Nongenomic actions of L-thyroxine and 3,5,3'-triiodo-L-thyronine. Focus on "L-Thyroxine vs. 3,5,3'-triiodo-L-thyronine and cell proliferation: activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase" Am J Physiol Cell Physiol, May 1, 2009; 296(5): C977 - C979. [Full Text] [PDF]