4-HPR modulates gene expression in ovarian cells.
Ovarian cancer has a high rate of recurrence and subsequent mortality following chemotherapy despite intense efforts to improve treatment outcomes. Recent trials have suggested that retinoids, especially 4-(N-hydroxyphenyl) retinamide (4-HPR), play an important role as a chemopreventive agent and are currently being used in clinical trials for ovarian cancer chemoprevention as well as treatment. This study examines the mechanism of its activity in premalignant and cancer cells. We investigated the modulation of gene expression by 4-HPR in immortalized ovarian surface epithelial (IOSE) cells and ovarian cancer (OVCA433) cells with DNA microarray. Real time RT-PCR and western blotting were used to confirm the microarray results and metabolic changes were examined with optical fluorescence spectroscopy. 4-HPR resulted in an up-regulation of expression of proapoptotic genes and mitochondrial uncoupling protein in OVCA433 cells and modulation of the RXR receptors in IOSE cells, and down-regulation of mutant BRCA genes in both IOSE and OVCA433 cells. 4-HPR had a larger effect on the redox in the 433 cells compared to IOSE. These findings suggest that 4-HPR acts through different mechanisms in premalignant ovarian surface cells and cancer cells, with a preventive effect in premalignant cells and a treatment effect in cancer cells.
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Arizona Cancer Center, Tucson, 85724, USA.
Molly
M
Brewer
Nathaniel D
ND
Kirkpatrick
J Taylor
JT
Wharton
Jian
J
Wang
Kenneth
K
Hatch
Nelly
N
Auersperg
Urs
U
Utzinger
David
D
Gershenson
Robert
R
Bast
Changping
C
Zou
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D002352:Carrier Proteins / Q000187:drug effects; D002453:Cell Cycle; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D017313:Fenretinide / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D019398:Genes, BRCA1 / Q000187:drug effects; D024522:Genes, BRCA2 / Q000187:drug effects; D006801:Humans; D007473:Ion Channels; D008565:Membrane Proteins / Q000187:drug effects; D024101:Mitochondrial Proteins; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000517:prevention & control; D047488:Retinoid X Receptors / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013050:Spectrometry, Fluorescence; D000071256:Uncoupling Protein 1; D015854:Up-Regulation / Q000187:drug effects
D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D047488:Retinoid X Receptors; D000071256:Uncoupling Protein 1; D017313:Fenretinide