Commutators of PAR-1 signaling in cancer cell invasion reveal an essential role of the Rho-Rho kinase axis and tumor microenvironment.
We recently reported that proteinase-activated receptors type I (PAR-1) are coupled to both negative and positive invasion pathways in colonic and kidney cancer cells cultured on collagen type I gels. Here, we found that treatments with the cell-permeant analog 8-Br-cGMP and the soluble guanylate cyclase activator BAY41-2272, and Rho kinase (ROK) inhibition by Y27632 or a dominant negative form of ROK lead to PAR-1-mediated invasion through differential Rac1 and Cdc42 signaling. Hypoxia or the counteradhesive matricellular protein SPARC/BM-40 (SPARC: secreted protein acidic rich in cysteine) overexpressed during cancer progression also commutated PAR-1 to cellular invasion through the cGMP/protein kinase G (PKG) cascade, RhoA inactivation, and Rac1-dependent or -independent signaling. Cultured primary cancer cells isolated from peritoneal and pleural effusions from patients with colon cancer or other malignant tumors harbored PAR-1, as shown by RT-PCR and FACS analyses. These malignant effusions also contained high levels of activated thrombin and fibrin, and induced a proinvasive response in HCT8/S11 human colorectal cancer cells. Our data underline the essential role of the tumor microenvironment and of several commutators targeting cGMP/PKG signaling and the RhoA-ROK axis in the control of PAR-1 proinvasive activity and metastatic potential of cancer cells in distant organs and peritoneal or pleural cavities. We also add new insights into the mechanisms linking the coagulation mediators thrombin and PAR-1 in the context of blood coagulation disorders and venous thrombosis often observed in cancer patients, as described in 1865 by Armand Trousseau.
Nguyen
Quang-Dé
QD
INSERM U673, Molecular and Clinical Oncology of Human Solid Tumors, Hôpital Saint-Antoine, 184 Rue du faubourg Saint-Antoine, 75571 Paris Cedex 12, France.
De Wever
Olivier
O
Bruyneel
Erik
E
Hendrix
An
A
Xie
Wan-Zhuo
WZ
Lombet
Alain
A
Leibl
Martin
M
Mareel
Marc
M
Gieseler
Frank
F
Bracke
Marc
M
Gespach
Christian
C
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D006152:Cyclic GMP / Q000502:physiology; D004285:Dogs; D051606:G-Protein-Coupled Receptor Kinase 1 / Q000037:antagonists & inhibitors / Q000502:physiology; D006162:Guanylate Cyclase; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D000860:Hypoxia / Q000201:enzymology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009369:Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D015676:Osteonectin / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D044463:Receptor, PAR-1 / Q000235:genetics / Q000502:physiology*; D011946:Receptors, Antigen / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000071756:Soluble Guanylyl Cyclase; D013917:Thrombin / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000502:physiology
D047908:Intracellular Signaling Peptides and Proteins; D015676:Osteonectin; D047428:Protein Kinase Inhibitors; D044463:Receptor, PAR-1; D011946:Receptors, Antigen; D018160:Receptors, Cytoplasmic and Nuclear; C028641:Tn receptor; C066737:RHOA protein, human; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D051606:G-Protein-Coupled Receptor Kinase 1; C496764:GRK1 protein, human; D013917:Thrombin; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP