Peroxisome proliferator-activated receptor gamma-mediated up-regulation of syndecan-1 by n-3 fatty acids promotes apoptosis of human breast cancer cells.
Diets enriched in n-3 polyunsaturated fatty acids (n-3 PUFA) may protect against breast cancer but biochemical mechanisms are unclear. Our studies showed that the n-3 fatty acid docosahexaenoic acid (DHA) up-regulated syndecan-1 (SDC-1) in human breast cancer cells, and we tested the hypothesis that DHA-mediated up-regulation of SDC-1 induces apoptosis. DHA was delivered to MCF-7 cells by n-3 PUFA-enriched low-density lipoproteins (LDL) or by albumin in the presence or absence of SDC-1 small interfering RNA. The n-3 PUFA induced apoptosis, which was blocked by SDC-1 silencing. We also confirmed that SDC-1 up-regulation and apoptosis promotion by n-3 PUFA was mediated by peroxisome proliferator-activated receptor gamma (PPAR gamma). Using a luciferase gene driven by either a PPAR response element or a DR-1 site present in the SDC-1 promoter, reporter activities were enhanced by n-3 LDL, DHA, and PPAR gamma agonist, whereas activity of a luciferase gene placed downstream of a mutant DR-1 site was unresponsive. Cotransfection with dominant-negative PPAR gamma DNA eliminated the increase in luciferase activity. These data provide strong evidence that SDC-1 is a molecular target of n-3 PUFA in human breast cancer cells through activation of PPAR gamma and that n-3 PUFA-induced apoptosis is mediated by SDC-1. This provides a novel mechanism for the chemopreventive effects of n-3 PUFA in breast cancer.
Sun
Haiguo
H
Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Berquin
Isabelle M
IM
Owens
Rick T
RT
O'Flaherty
Joseph T
JT
Edwards
Iris J
IJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology*; D005260:Female; D005395:Fish Oils; D006801:Humans; D047495:PPAR gamma / Q000502:physiology*; D016133:Polymerase Chain Reaction; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D053668:Syndecan-1 / Q000235:genetics*
D000970:Antineoplastic Agents; D015525:Fatty Acids, Omega-3; D005395:Fish Oils; D047495:PPAR gamma; D012334:RNA, Neoplasm; D053668:Syndecan-1