Exp Mol Med.  2009 Sep;41(9):678-685. 10.3858/emm.2009.41.9.074.

Triptolide-induced suppression of phospholipase D expression inhibits proliferation of MDA-MB-231 breast cancer cells

• Kang DW
• Lee JY
• Oh DH
• Park SY
• Woo TM
• Kim MK
• Park MH
• Jang YH
• Min DS

• KMID: 756211
• DOI: http://doi.org/10.3858/emm.2009.41.9.074

Abstract

In spite of the importance of phospholipase D (PLD) in cell proliferation and tumorigenesis, little is known about the molecules regulating PLD expression. Thus, identification of small molecules inhibiting PLD expression would be an important advance for PLD-mediated physiology. We examined one such here, denoted "Triptolide", which was identified in a chemical screen for inhibitors of PLD expression using cell assay system based on measurement of PLD promoter activity. Triptolide significantly suppressed the expression of both PLD1 and PLD2 with sub-microM potency in MDA-MB-231 breast cancer cells as analyzed by promoter assay and RT-PCR. Moreover, triptolide abolished the protein level of PLD in a time and dose-dependent manner. Triptolide-induced PLD1 downregulation was also observed in all the cancer cells examined, suggesting a general phenomenon detected in various cancer cells. Decrease of PLD expression by triptolide suppressed both basal and PMA-induced PLD activity. In addition, triptolide inhibited activation of NFkappaB which increased PLD1 expression. Ultimately, downregulation of PLD by triptolide inhibited proliferation of breast cancer cells. Taken together, we demonstrate that triptolide suppresses the expression of PLD via inhibition of NFkappaB activation and then decreases cell proliferation.

Keyword

breast neoplasms; cell proliferation; gene expression regulation, neoplastic; NF-kappaB; phospholipase D; triptolide

MeSH Terms

Antineoplastic Agents, Alkylating/*pharmacology
Breast Neoplasms/drug therapy/enzymology
Cell Line, Tumor
Cell Proliferation/drug effects
Diterpenes/*pharmacology
Epoxy Compounds/pharmacology
Female
Gene Expression Regulation, Neoplastic/*drug effects
Humans
NF-kappa B/genetics/metabolism
Phenanthrenes/*pharmacology
Phospholipase D/*genetics/metabolism