Protease‐activated receptor (PAR)‐1 and PAR‐2 participate in the cell growth of alveolar capillary endothelium in primary lung adenocarcinomas

Jin, Enjing; Fujiwara, Masakazu; Xin, Pan; Ghazizadeh, Mohammad; Arai, Satoru; Ohaki, Yoshiharu; Kajiwara, Keiko; Takemura, Tamiko; Kawanami, Oichi

doi:10.1002/cncr.11087

Cited by 64 publications

(26 citation statements)

References 62 publications

(45 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PAR is a G-protein coupled receptor that is expressed in many cancer cells and cells in the microenvironment of a tumor. It can be activated by serine proteases like trypsin 74 and thrombin 75 by cleavage of its extracellular segment and transmit intracellular signals to stimulate cancer cell growth 76-78. A comprehensive review on hKs and its role in cancer with tabulated clinical implications are found in references 15 and 58, respectively.…”

Section: Target Proteasesmentioning

confidence: 99%

Protease-Activated Drug Development

Choi¹,

Swierczewska²,

Lee³

et al. 2012

Theranostics

209

189

View full text Add to dashboard Cite

In this extensive review, we elucidate the importance of proteases and their role in drug development in various diseases with an emphasis on cancer. First, key proteases are introduced along with their function in disease progression. Next, we link these proteases as targets for the development of prodrugs and provide clinical examples of protease-activatable prodrugs. Finally, we provide significant design considerations needed for the development of the next generation protease-targeted and protease-activatable prodrugs.

show abstract

Section: Target Proteasesmentioning

confidence: 99%

Protease-Activated Drug Development

Choi¹,

Swierczewska²,

Lee³

et al. 2012

Theranostics

209

189

View full text Add to dashboard Cite

show abstract

“…This transactivation of the EGF-R by PAR2 agonists has never been reported before in any cell system. Whether this mechanism can be extended to other cancers such as gastric carcinoma (23), melanoma (24), lung carcinoma (25), pancreatic cancer (26), or glioblastoma (27) in which trypsin promotes cell proliferation remains to be established.…”

Section: Par2 Transactivates Egf-r In Colon Cancermentioning

confidence: 99%

Protease-activated Receptor 2 in Colon Cancer

Darmoul

Gratio

Devaud

et al. 2004

Journal of Biological Chemistry

189

View full text Add to dashboard Cite

Several lines of evidence suggest that tumor-derived trypsin contributes to the growth and invasion of cancer cells. We have recently shown that trypsin is a potent growth factor for colon cancer cells through activation of the G protein-coupled receptor protease-activated receptor 2 (PAR2). Here, we analyzed the signaling pathways downstream of PAR2 activation that lead to colon cancer cell proliferation in HT-29 cells. Our data are consistent with the following cascade of events upon activation of PAR2 by the serine protease trypsin or the specific PAR2-activating peptide (AP2): (i) a matrix metalloproteinasedependent release of transforming growth factor (TGF)-␣, as demonstrated with TGF-␣-blocking antibodies and measurement of TGF-␣ in culture medium; (ii) TGF-␣-mediated activation of epidermal growth factor receptor (EGF-R) and subsequent EGF-R phosphorylation; and (iii) activation of ERK1/2 and subsequent cell proliferation. The links between these events are demonstrated by the fact that stimulation of cell proliferation and ERK1/2 upon activation of PAR2 is reversed by the metalloproteinase inhibitor batimastat, TGF-␣-neutralizing antibodies, EGF-R ligand binding domain-blocking antibodies, and the EGF-R tyrosine kinase inhibitors AG1478 and PD168393. Therefore, transactivation of EGF-R appears to be a major mechanism whereby activation of PAR2 results in colon cancer cell growth. By using the Src tyrosine kinase inhibitor PP2, we further showed that Src plays a permissive role for PAR2-mediated ERK1/2 activation and cell proliferation, probably acting downstream of the EGF-R. These data explain how trypsin exerts robust trophic action on colon cancer cells and underline the critical role of EGF-R transactivation.Proteases have been increasingly recognized as important factors in pathophysiology of tumor diseases. Besides their contribution to cancer progression by the degradation of extracellular matrix proteins, there is now substantial evidence that certain proteases serve as signal molecules controlling cell functions through specific membrane receptors, the proteaseactivated receptors. PARs 1 are seven transmembrane-spanning domain G protein-coupled receptors comprising four receptors named PAR1, PAR2, PAR3, and PAR4 (1, 2). Thrombin is the physiological activator of PAR1, PAR3, and PAR4, whereas PAR2 is activated by multiple trypsin-like enzymes including trypsin and mast cell tryptase but not thrombin. The mechanism of activation of PARs was initially established for PAR1 (3) and seems to be a paradigm for the other PARs (1, 2, 4). They are irreversibly activated by a proteolytic mechanism in which the protease binds to and cleaves the amino-terminal exodomain of the receptor. This cleavage generates a new amino-terminal sequence that binds intramolecularly to the core receptor and serves as a tethered ligand. Synthetic activating peptides that mimic the tethered ligand domains of PAR1, PAR2, and PAR4 have been developed. The activation of PARs by these synthetic peptides APs is independent of rec...

show abstract

“…TNF-α, triggered by the degranulation of MCs, induced ICAM-1 overexpression and facilitated the migration of neutrophils through the endogenously generated or exogenous chemokines KC/CXCL1 and LIX/CXCL5 [15]. MC tryptase was considered as one of the ligand enzymes for protease-activated receptor 2 (PAR-2) which was abundantly expressed in the airways [50]. Tryptase-mediated PAR-2 activation induced various lung disorders [51].…”

Section: Discussionmentioning

confidence: 99%

Mast Cell Stabilization Alleviates Acute Lung Injury after Orthotopic Autologous Liver Transplantation in Rats by Downregulating Inflammation

et al. 2013

View full text Add to dashboard Cite

BackgroundAcute lung injury (ALI) is one of the most severe complications after orthotopic liver transplantation. Amplified inflammatory response after transplantation contributes to the process of ALI, but the mechanism underlying inflammation activation is not completely understood. We have demonstrated that mast cell stabilization attenuated inflammation and ALI in a rodent intestine ischemia/reperfusion model. We hypothesized that upregulation of inflammation triggered by mast cell activation may be involve in ALI after liver transplantation.MethodsAdult male Sprague–Dawley rats received orthotopic autologous liver transplantation (OALT) and were executed 4, 8, 16, and 24 h after OALT. The rats were pretreated with the mast cell stabilizers cromolyn sodium or ketotifen 15 min before OALT and executed 8 h after OALT. Lung tissues and arterial blood were collected to evaluate lung injury. β-hexosaminidase and mast cell tryptase levels were assessed to determine the activation of mast cells. Tumor necrosis factor α (TNF-α), interleukin (IL)-1β and IL-6 in serum and lung tissue were analyzed by enzyme-linked immunosorbent assay. Nuclear factor-kappa B (NF-κB) p65 translocation was assessed by Western blot.ResultsThe rats that underwent OALT exhibited severe pulmonary damage with a high wet-to-dry ratio, low partial pressure of oxygen, and low precursor surfactant protein C levels, which corresponded to the significant elevation of pro-inflammatory cytokines, β-hexosaminidase, and tryptase levels in serum and lung tissues. The severity of ALI progressed and maximized 8 h after OALT. Mast cell stabilization significantly inhibited the activation of mast cells, downregulated pro-inflammatory cytokine levels and translocation of NF-κB, and attenuated OALT-induced ALI.ConclusionsMast cell activation amplified inflammation and played an important role in the process of post-OALT related ALI.

show abstract

Protease‐activated receptor (PAR)‐1 and PAR‐2 participate in the cell growth of alveolar capillary endothelium in primary lung adenocarcinomas

Cited by 64 publications

References 62 publications

Protease-Activated Drug Development

Protease-Activated Drug Development

Protease-activated Receptor 2 in Colon Cancer

Mast Cell Stabilization Alleviates Acute Lung Injury after Orthotopic Autologous Liver Transplantation in Rats by Downregulating Inflammation

Contact Info

Product

Resources

About