Signaling from protease-activated receptor-1 inhibits migration and invasion of breast cancer cells

Citation
L. Kamath et al., Signaling from protease-activated receptor-1 inhibits migration and invasion of breast cancer cells, CANCER RES, 61(15), 2001, pp. 5933-5940
Citations number
36
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
CANCER RESEARCH
ISSN journal
00085472 → ACNP
Volume
61
Issue
15
Year of publication
2001
Pages
5933 - 5940
Database
ISI
SICI code
0008-5472(20010801)61:15<5933:SFPRIM>2.0.ZU;2-1
Abstract
Proteases give cancer a defining characteristic of being able to break thro ugh extracellular matrix barriers and invade into other tissues in response to chemotactic signals. Recently, the cell surface protease-activated rece ptor (PAR)-1 has been shown to act as a chemokine receptor in inflammatory cells, and its expression is tightly correlated with metastatic propensity of breast cancer cells. The aim of the present study was to determine wheth er activation of PAR1 or the other known PARS (PAR2-4) can regulate migrati on and invasion of breast cancer cells. We found that the highly invasive M DAMB231 breast cancer cell line expressed very high levels of functional PA RI, PAR2, and PAR4, whereas minimally invasive MCF7 cells had trace amounts of PARI and low levels of PAR2 and PAR4. Despite the differences in expres sion, PAR2 and PAR4 acted as chemokine receptors in both invasive and minim ally invasive breast cell lines. Quite unexpectedly, we found that activati on of PAR1 with thrombin or the peptide agonist SFLLRN markedly inhibited i nvasion and migration of MDAMB231 cells when applied as a concentration gra dient in the direction of cell movement. Additionally, we demonstrated that inhibition of chemotaxis was mediated through a G(i)/phosphoinositide-3-OH kinase-dependent pathway. Activation of G(i) signaling with epinephrine or wasp venom mastoparan also inhibited invasion and migration of the breast cancer cells. These findings suggest that therapeutics targeted toward G(i) -couplers that are selectively expressed in breast cancer cells could prove beneficial in halting the progression of invasive breast cancer.