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-mM 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 NFkB 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.
Highlights
Triptolide is a natural, biologically active compound as a diterpenoid triepoxide originally purified from the Chinese herb Tripterygium wilfordii Hook F (TWHF)
We found that triptolide inhibited the expression and activity of phospholipase D (PLD) in MDA-MB-231 human breast cancer cell which is highly invasive and has high level of PLD activity (Chen et al, 2003, 2005)
Since PLD has emerged as a critical regulator of cell proliferation and survival (Foster and Xu, 2003), we tried to screen small molecules inhibiting the expression of PLD using cell assay system for measurement of PLD promoter activity
Summary
Triptolide is a natural, biologically active compound as a diterpenoid triepoxide originally purified from the Chinese herb Tripterygium wilfordii Hook F (TWHF). This natural product used in traditional Chinese medicine for centuries, has a myriad of therapeutic uses against inflammation and autoimmune disease (Chen, 2001; Qiu et al, 2003, Xiang and Zhang, 2005). Anti-inflammatory and anti-proliferative properties of triptolide have been associated with inhibition of NFκB (Lee et al, 1999; Qiu et al, 1999; Liu et al, 2000). The exact targets and molecular mechanism of action of triptolide are still unknown
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