chapter
TDAG8-mediated intracellular signaling pathways and its function on tumor
ByQ. Xi, D. Yang, L. Bao, Narengerile & A. Damirin
Pages 4

It has been proved that pH value of the tumor microenvironment is lower than normal tissues, and sometimes the pH value can go down to 5.8∼5.4 (Izumi et al. 2003, Yoneda et al. 2011). In the process of malignant tumor growth, the poor development of tumor blood vessels and the fast increase of hyperblastosis caused severe hypoxemia of local tissues and enhance the glycolysis/ lactic acid metabolism. Through improving glucose transport, glycolysis and formation system of tumor blood vessels, tumor cells had tolerance and adaptability to the hypoxic-ischemic environment. The key factor mediated tumor cells and hypoxia environment was HIF-1α (hypoxia-inducible factor-1α). HIF-1α can induce the expression of glycolytic and related enzymes, GLUTl (glucose transporter 1) and VEGF (vascular endothelial growth factor) to absorb glucose from the extracellular environment for glycolysis and to maintain the energy metabolism of the tumor on the one hand. On the other hand, HIF-1α can promote the new angiogenesis, accelerate the tumor cell proliferation, and increase blood-supply, oxygensupply and energy-supply (Fang et al. 2008). New blood vessels formation and the enhanced activity of glycolysis are substantial two major characteristics of malignant tumor, and these two features allow tumor cells to adapt to the hypoxia environment (Herota & Semenza 2006). Glycolysis produced large amounts of lactic acid, pyruvic acid, etc (Robergs et al. 2004, Kennedy & Dawhirst 2010). In practice, however, the intracellular pH

1 INTRODUCTION

TDAG8 (T-cell death-associated gene 8) is named because of its high expression in the T lymphocyte apoptosis process, and it may be involved in activation-induced T-cell death (Choi et al. 1996, Tomura et al. 2005). Human TDAG8 gene is located on q31-32.1 region of chromosome 14, and the total length is 1787 bp including one exon and two introns. The exon is 1014 bp long and encoded 337 amino acids (Kyaw et al. 1998). TDAG8 generally exists in the peripheral blood leukocytes, spleen, lymph nodes, thymus, THP1 and HL60 cell line, macrophages and some tumor tissues, and coupled with known G proteins such as Gs (Sin et al. 2004). In 2001, it was found that psychosine was the lipid ligand of TDAG8 through a large number of experiments, and its structure was similar to lysophospholipids, which could activate TDAG8 (Im et al. 2001). In 2004, TDAG8 was regarded as a proton ligand, and TDAG8 could sense extracellular protons in acidic environments so as to activate a series of intracellular signaling pathways (Wang et al. 2004).