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PMID: 20536428 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Modulation of mammary cancer cell migration by 15-deoxy-delta(12,14)-prostaglandin J(2): implications for anti-metastatic therapy.

The Biochemical journal ·Vol. 430 ·No. 1 ·2010-08-15 ·Pages 69-78

Diers AR, Dranka BP, Ricart KC, Oh JY, Johnson MS, Zhou F, Pallero MA, Bodenstine TM, Murphy-Ullrich JE, Welch DR, Landar A

Abstract

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.

MeSH Terms
Actins/physiology Adaptor Proteins, Signal Transducing/physiology Animals Antineoplastic Agents/pharmacology Cell Line, Tumor Cell Movement/drug effects Cell Survival/drug effects Cytoskeletal Proteins/physiology Focal Adhesion Kinase 1/physiology Focal Adhesions/drug effects Kelch-Like ECH-Associated Protein 1 Mice Neoplasm Metastasis/drug therapy Prostaglandin D2/analogs & derivatives,pharmacology Signal Transduction p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors
Chemicals
15-deoxy-delta(12,14)-prostaglandin J2 Actins Adaptor Proteins, Signal Transducing Antineoplastic Agents Cytoskeletal Proteins Keap1 protein, mouse Kelch-Like ECH-Associated Protein 1 Focal Adhesion Kinase 1 Ptk2 protein, mouse p38 Mitogen-Activated Protein Kinases Prostaglandin D2
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Diers Anne R
Department of Pathology, University of Alabama at Birmingham, 35294-0022, USA.
Dranka Brian P
Ricart Karina C
Oh Joo Yeun
Johnson Michelle S
Zhou Fen
Pallero Manuel A
Bodenstine Thomas M
Murphy-Ullrich Joanne E
Welch Danny R
Landar Aimee
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Article Info
Journal
The Biochemical journal
Abbr.
Biochem J
ISSN
1470-8728
DOI
10.1042/BJ20091193
Published
2010-08-15
Pages
69-78
Language
English
Region
England
NLM ID
2984726R
PMCID
PMC2963584
Subset
IM
Grants
NHLBI NIH HHS · R01 HL079644-01A2 · United States
NCI NIH HHS · R01 CA087728 · United States
NCI NIH HHS · R01 CA87728 · United States
NHLBI NIH HHS · T32 HL007918-13 · United States
NHLBI NIH HHS · T32 HL007918 · United States
NHLBI NIH HHS · R01 HL079644 · United States
NCI NIH HHS · R01 CA087728-09S1 · United States
External Links
PubMed source DOI: 10.1042/BJ20091193 PMC Full Text View journal details
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