Effects of 15-deoxy-delta 12, 14-prostaglandin J2 on the expression of p53 in MCF-7 cells.
Cyclopentenone prostaglandins (cyPGs) exert diverse cellular functions, such as anti-inflammatory and cytoprotective effects, via multiple mechanisms. CyPGs, especially those of the A and J series, are characterized by the presence of a chemically reactive alpha,beta-unsaturated carbonyl group. 15-Deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), a representative cyPG of the J series, has been reported to directly inhibit the activity of redox-sensitive transcription factors, such as activator protein-1 and nuclear factor-kappaB. In the present study, we examined the effects of 15d-PGJ(2) on activation of p53 tumor suppressor in human breast cancer (MCF-7) cells. MCF-7 cells treated with 15d-PGJ(2) exhibited elevated p53 protein expression in time- and concentration-related manners, whereas prostaglandin A(2) (PGA(2)) and the nonprostaglandin derivative 2-cyclopenten-1-one exerted an effect to a lesser extent than did 15d-PGJ(2). In addition, MCF-7 cells exposed to 15d-PGJ(2) significantly accumulated p53 in both cytosolic and nuclear fractions. Despite the elevated levels of p53, its DNA-binding activity was reduced in 15d-PGJ(2)-treated MCF-7 cells. Moreover, isolated MCF-7 nuclear extracts directly treated with 15d-PGJ(2) exhibite diminished DNA-binding ability of p53, while the same concentration of PGA(2) or 2-cyclopenten-1-one was much less inhibitory. Thus, the electrophilic carbon center located in the alpha,beta-unsaturated carbonyl moiety of the cyclopentenone ring might be critical for the control of DNA-binding activity as well as cellular levels of p53 by 15d-PGJ(2).
Kim
Do-Hee
DH
National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy, Seoul National University, Seoul, Korea.
Kim
Eun-Hee
EH
Na
Hye-Kyung
HK
Surh
Young-Joon
YJ
D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D002474:Cell-Free System / Q000737:chemistry / Q000378:metabolism; D003517:Cyclopentanes / Q000737:chemistry / Q000494:pharmacology; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D018613:Microscopy, Confocal; D015394:Molecular Structure; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D011454:Prostaglandins A / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D003517:Cyclopentanes; D011454:Prostaglandins A; D016159:Tumor Suppressor Protein p53; C100008:prostaglandin A2; C013905:cyclopentenone; D015230:Prostaglandin D2