Autocrine/paracrine prostaglandin E2 production by non-small cell lung cancer cells regulates matrix metalloproteinase-2 and CD44 in cyclooxygenase-2-dependent invasion.
Tumor cyclooxygenase-2 (COX-2) expression is known to be associated with enhanced tumor invasiveness. In the present study, we evaluated the importance of the COX-2 product prostaglandin E2 (PGE2) and its signaling through the EP4 receptor in mediating non-small cell lung cancer (NSCLC) invasiveness. Genetic inhibition of tumor COX-2 led to diminished matrix metalloproteinase (MMP)-2, CD44, and EP4 receptor expression and invasion. Treatment of NSCLC cells with exogenous 16,16-dimethylprostaglandin E2 significantly increased EP4 receptor, CD44, and MMP-2 expression and matrigel invasion. In contrast, anti-PGE2 decreased EP4 receptor, CD44, and MMP-2 expression in NSCLC cells. EP4 receptor signaling was found to be central to this process, because antisense oligonucleotide-mediated inhibition of tumor cell EP4 receptors significantly decreased CD44 expression. In addition, agents that increased intracellular cAMP, as is typical of EP4 receptor signaling, markedly increased CD44 expression. Moreover, MMP-2-AS treatment decreased PGE2-mediated CD44 expression, and CD44-AS treatment decreased MMP-2 expression. Thus, PGE2-mediated effects through EP4 required the parallel induction of both CD44 and MMP-2 expression because genetic inhibition of either MMP-2 or CD44 expression effectively blocked PGE2-mediated invasion in NSCLC. These findings indicate that PGE2 regulates COX-2-dependent, CD44- and MMP-2-mediated invasion in NSCLC in an autocrine/paracrine manner via EP receptor signaling. Thus, blocking PGE2 production or activity by genetic or pharmacological interventions may prove to be beneficial in chemoprevention or treatment of NSCLC.
Dohadwala
Mariam
M
Lung Cancer Research Program of the UCLA Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.
Batra
Raj K
RK
Luo
Jie
J
Lin
Ying
Y
Krysan
Kostyantyn
K
Pold
Mehis
M
Sharma
Sherven
S
Dubinett
Steven M
SM
D015703:Antigens, CD / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000502:physiology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism*; D008175:Lung Neoplasms; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D008565:Membrane Proteins; D009361:Neoplasm Invasiveness; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D020239:Receptor Cross-Talk; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D018960:Hyaluronan Receptors; D007527:Isoenzymes; D008565:Membrane Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020778:Matrix Metalloproteinase 2; D015232:Dinoprostone