Blockade of PAR1 signaling with cell-penetrating pepducins inhibits Akt survival pathways in breast cancer cells and suppresses tumor survival and metastasis.
Protease-activated receptor 1 (PAR1) is a G protein-coupled receptor that is not expressed in normal breast epithelia but is up-regulated in invasive breast carcinomas. In the present study, we found that matrix metalloprotease-1 (MMP-1) robustly activates the PAR1-Akt survival pathway in breast carcinoma cells. This process is blocked by a cell-penetrating lipopeptide "pepducin," P1pal-7, which is a potent inhibitor of cell viability in breast carcinoma cells expressing PAR1. Both a MMP-1 inhibitor and P1pal-7 significantly promote apoptosis in breast tumor xenografts and inhibit metastasis to the lungs by up to 88%. Dual therapy with P1pal-7 and Taxotere inhibits the growth of MDA-MB-231 xenografts by 95%. Consistently, biochemical analysis of xenograft tumors treated with P1pal-7 or MMP-1 inhibitor showed attenuated Akt activity. Ectopic expression of constitutively active Akt rescues breast cancer cells from the synergistic cytotoxicity of P1pal-7 and Taxotere, suggesting that Akt is a critical component of PAR1-dependent cancer cell viability. Together, these findings indicate that blockade of MMP1-PAR1 signaling may provide a benefit beyond treatment with Taxotere alone in advanced, metastatic breast cancer.
Yang
Eric
E
Division of Hematology/Oncology, Molecular Oncology Research Institute, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
Boire
Adrienne
A
Agarwal
Anika
A
Nguyen
Nga
N
O'Callaghan
Katie
K
Tu
Powen
P
Kuliopulos
Athan
A
Covic
Lidija
L
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D000077143:Docetaxel; D004357:Drug Synergism; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008819:Mice, Nude; D010455:Peptides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D044463:Receptor, PAR-1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D043823:Taxoids / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays; D010975:Platelet Aggregation Inhibitors
D061965:Matrix Metalloproteinase Inhibitors; D010455:Peptides; D034741:RNA, Small Interfering; D044463:Receptor, PAR-1; D043823:Taxoids; D000077143:Docetaxel; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1; D010975:Platelet Aggregation Inhibitors