RhoA mediates cyclooxygenase-2 signaling to disrupt the formation of adherens junctions and increase cell motility.
Cyclooxygenase-2 (COX-2) represents an important target for treatment and prevention of colorectal cancer. Although COX-2 signaling is implicated in promoting tumor cell growth and invasion, the molecular mechanisms that mediate these processes are largely unknown. In this study, we show that the RhoA pathway mediates COX-2 signaling to disrupt the formation of adherens junctions and increase cell motility. Disruption of adherens junctions promotes tumor cell invasion and metastasis and is often associated with tumor progression. We detected high levels of RhoA activity in HCA-7 colon carcinoma cells that constitutively express COX-2. Inhibition of COX-2 significantly reduced the levels of RhoA activity in HCA-7 cells, suggesting that constitutive expression of COX-2 stimulates RhoA activity. Interestingly, inhibition of COX-2 or silencing of COX-2 expression with small interfering RNA (siRNA) stimulated the formation of adherens junctions, concomitant with increased protein levels of E-cadherin and alpha-catenin. Furthermore, inhibition of RhoA or silencing of RhoA expression with siRNA increased the levels of E-cadherin and alpha-catenin. Inhibition of Rho kinases (ROCK), the RhoA effector proteins, also increased levels of E-cadherin and alpha-catenin and stimulated formation of adherens junctions. The motility of HCA-7 cells was significantly decreased when COX-2 or RhoA was inhibited. Therefore, our data reveal a novel molecular mechanism that links COX-2 signaling to disrupt the formation of adherens junctions; COX-2 stimulates the RhoA/ROCK pathway, which reduces levels of E-cadherin and alpha-catenin leading to disruption of adherens junction formation and increased motility. Understanding of COX-2 downstream signaling pathways that promote tumor progression is crucial for the development of novel therapeutic strategies.
Chang
Yu-Wen E
YW
Department of Biochemistry, Kansas City University of Medicine and Biosciences, Kansas City, Missouri 64106, USA.
Marlin
Jerry W
JW
Chance
Terry W
TW
Jakobi
Rolf
R
D022005:Adherens Junctions / Q000502:physiology*; D002455:Cell Division; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D003110:Colonic Neoplasms / Q000473:pathology* / Q000503:physiopathology; D015179:Colorectal Neoplasms / Q000473:pathology* / Q000503:physiopathology; D051546:Cyclooxygenase 2 / Q000502:physiology*; D020868:Gene Silencing; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D009361:Neoplasm Invasiveness; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D020742:rhoA GTP-Binding Protein / Q000502:physiology*
D008565:Membrane Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D020742:rhoA GTP-Binding Protein