Gamma tocopherol upregulates the expression of 15-S-HETE and induces growth arrest through a PPAR gamma-dependent mechanism in PC-3 human prostate cancer cells.
Chronic inflammation and dietary fat consumption correlates with an increase in prostate cancer. Our previous studies in the colon have demonstrated that gamma-tocopherol treatment could upregulate the expression of peroxisome proliferator-activated preceptors (PPAR) gamma, a nuclear receptor involved in fatty acid metabolism as well modulation of cell proliferation and differentiation. In this study, we explored the possibility that gamma-tocopherol could induce growth arrest in PC-3 prostate cancer cells through the regulation of fatty acid metabolism. Growth arrest (40%) and PPAR gamma mRNA and protein upregulation was achieved with gamma-tocopherol within 6 h. gamma-Tocopherol-mediated growth arrest was demonstrated to be PPAR gamma dependent using the agonist GW9662 and a PPAR gamma dominant negative vector. gamma-tocopherol was shown not to be a direct PPAR gamma ligand, but rather 15-S-HETE (an endogenous PPAR gamma ligand) was upregulated by gamma-tocopherol treatment. 15-Lipoxygenase-2, a tumor suppressor and the enzyme that converts arachidonic acid to 15-S-HETE, was upregulated at 3 h following gamma-tocopherol treatment. Expression of proteins downstream of the PPAR gamma pathway were examined. Cyclin D1, cyclin D3, bcl-2, and NFkappa B proteins were found to be downregulated following gamma-tocopherol treatment. These data demonstrate that the growth arrest mediated by gamma-tocopherol follows a PPAR-gamma-dependent mechanism.
Department of Biochemistry, East Tennessee State University, Johnson City, TN 37614, USA. campbese@etsu.edu
Sharon E
SE
Campbell
Phillip R
PR
Musich
Sarah G
SG
Whaley
Julie B
JB
Stimmel
Lisa M
LM
Leesnitzer
Sophie
S
Dessus-Babus
Michelle
M
Duffourc
William
W
Stone
Robert A
RA
Newman
Peiying
P
Yang
Koyamangalath
K
Krishnan
D000230:Adenocarcinoma / Q000473:pathology; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004847:Epithelial Cells; D015870:Gene Expression / Q000187:drug effects*; D055786:Gene Knockout Techniques; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000737:chemistry / Q000378:metabolism*; D008024:Ligands; D008297:Male; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D011467:Prostate / Q000166:cytology; D011471:Prostatic Neoplasms / Q000473:pathology*; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D024504:gamma-Tocopherol / Q000378:metabolism / Q000494:pharmacology*
D006893:Hydroxyeicosatetraenoic Acids; D008024:Ligands; D047495:PPAR gamma; D012333:RNA, Messenger; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D024504:gamma-Tocopherol; C458528:ALOX15B protein, human; D001093:Arachidonate 15-Lipoxygenase