Involvement of store-operated calcium signaling in EGF-mediated COX-2 gene activation in cancer cells

• Published in: Cellular signalling 2012-01, Vol.24 (1), p.162-169
• Main Authors: Wang, Jaw-Yuan, Chen, Ben-Kuen, Wang, Yu-Shiuan, Tsai, Yao-Ting, Chen, Wei-Chiao, Chang, Wen-Chang, Hou, Ming-Feng, Wu, Yang-Chang, Chang, Wei-Chiao
• Format: Article
• Language: English
• Subjects: Boron Compounds - pharmacology; Calcium - pharmacology; Calcium - physiology; Calcium Channel Blockers - pharmacology; Calcium channels; Calcium Channels - genetics; Calcium Channels - metabolism; Calcium influx; Calcium Signaling; Cell Line, Tumor; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Cyclic AMP response element-binding protein; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; Cyclooxygenase-2; EGF; Epidermal Growth Factor - pharmacology; Epidermal Growth Factor - physiology; Epidermal growth factor receptors; Gene Expression; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Inflammation; Membrane Proteins - genetics; Membrane Proteins - metabolism; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; NF-AT protein; ORAI1 Protein; ORAI1/CRACM1; Promoters; Receptor, Epidermal Growth Factor - agonists; Receptor, Epidermal Growth Factor - metabolism; Regulatory sequences; Response Elements; RNA Interference; Signal transduction; siRNA; Solid tumors; STIM1; STIM1 protein; Store-operated calcium channel; Stromal Interaction Molecule 1; Transcription activation; Transcription factors; Transfection; Tumorigenesis
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2011.08.017

Growing evidence shows that chronic inflammation drives the progression of colorectal cancer (CRC). Cyclooxygenase-2 (COX-2) is one of the most important inflammatory genes involved in solid tumor metastasis. Epidermal growth factor receptor (EGFR) also plays a key role in cancer cell development. We compared the expression levels of EGFR and COX-2 between tumor and normal tissues from 20 CRC patients and studied the molecular mechanism of EGFR-mediated COX-2 gene expression in cancer cells. Our results indicated that COX-2 expression was markedly increased after EGF stimulation. COX-2 promoter analysis indicated the involvement of cyclic AMP-responsive element (CRE) and nuclear factor of activated T cells/nuclear factor interleukin-6 (NFAT/NF-IL6)-binding sites in EGF-mediated signaling pathways. Furthermore, EGF-mediated COX-2 activation was prevented by 2-aminoethoxydiphenyl borate (2-APB), a store-operated Ca2+ channel inhibitor. Transfection of siRNA against ORAI1 or STIM1, the key regulators of store-operated Ca2+ channels, showed significant inhibitory effects on EGF-mediated COX-2 expression. In conclusion, store-operated Ca2+ entry is involved in the activation of transcription factors (CREB/NFAT) that are responsible for delivering EGF-mediated signals to evoke inflammatory cascades and is eventually related to CRC tumorigenesis. ► Colorectal cancer (CRC) patients whose tumor tissues highly expressed both EGFR and COX-2. ► EGF-mediated COX-2 activation was prevented by 2-APB, a store-operated Ca2+ channel inhibitor. ► siRNA against ORAI1 or STIM1 showed significant inhibitory effects on EGF-mediated COX-2 expression.