Modulation of mammary cancer cell migration by 15-deoxy-delta(12,14)-prostaglandin J(2): implications for anti-metastatic therapy.
Recently, a number of steps in the progression of metastatic disease have been shown to be regulated by redox signalling. Electrophilic lipids affect redox signalling through the post-translational modification of critical cysteine residues in proteins. However, the therapeutic potential as well as the precise mechanisms of action of electrophilic lipids in cancer cells is poorly understood. In the present study, we investigate the effect of the electrophilic prostaglandin 15d-PGJ2 (15-deoxy-Delta12,14-prostaglandin J2) on metastatic properties of breast cancer cells. 15d-PGJ2 was shown to decrease migration, stimulate focal-adhesion disassembly and cause extensive F-actin (filamentous actin) reorganization at low concentrations (0.03-0.3 microM). Importantly, these effects seem to be independent of PPARgamma (peroxisome-proliferator-activated receptor gamma) and modification of actin or Keap1 (Kelch-like ECH-associated protein 1), which are known protein targets of 15d-PGJ2 at higher concentrations. Interestingly, the p38 inhibitor SB203580 was able to prevent both 15d-PGJ2-induced F-actin reorganization and focal-adhesion disassembly. Taken together, the results of the present study suggest that electrophiles such as 15d-PGJ2 are potential anti-metastatic agents which exhibit specificity for migration and adhesion pathways at low concentrations where there are no observed effects on Keap1 or cytotoxicity.
Department of Pathology, University of Alabama at Birmingham, 35294-0022, USA.
Anne R
AR
Diers
Brian P
BP
Dranka
Karina C
KC
Ricart
Joo Yeun
JY
Oh
Michelle S
MS
Johnson
Fen
F
Zhou
Manuel A
MA
Pallero
Thomas M
TM
Bodenstine
Joanne E
JE
Murphy-Ullrich
Danny R
DR
Welch
Aimee
A
Landar
D000199:Actins / Q000502:physiology; D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000502:physiology; D051417:Focal Adhesion Kinase 1 / Q000502:physiology; D022001:Focal Adhesions / Q000187:drug effects; D000072019:Kelch-Like ECH-Associated Protein 1; D051379:Mice; D009362:Neoplasm Metastasis / Q000188:drug therapy; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D003598:Cytoskeletal Proteins; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases; D015230:Prostaglandin D2