|Wang, Thomas - Tom|
|KIM, E - National Cancer Institute (NCI, NIH)|
|KIM, YOUNG - National Cancer Institute (NCI, NIH)|
Submitted to: Molecular Carcinogenesis
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/19/2012
Publication Date: 4/11/2012
Citation: Wang, T.T., Schoene, N.W., Kim, E.K., Kim, Y.S. 2012. Pleiotropic effects of the sirtuin inhibitor sirtinol involves concentration-dependent modulation of multiple nuclear receptor-mediated pathways in the androgen-responsive prostate cancer cell LNCaP. Molecular Carcinogenesis. DOI:10.1002/mc.21906.
Interpretive Summary: Sirtinol is a compound found in plants that is considered a polyphenol that is a specific inhibitor of sirtuin. When activated in the body, sirtuins are thought to contribute to the plant’s ability to prevent cancer development. Sirtinol has been used extensively as a tool to identify compounds that can prevent cancer or be used in cancer therapy that exert their activity through altering sirtuin. The specific role in cellular pathways of sirtinol, other than serving as an inhibitor of sirtuin in cells, is less clear. The present study addressed this deficiency in the literature. Based on structural similarity with plant-derived cancer preventive/therapeutic compounds such as 3’, 3’-diindolylmethane, resveratrol and genistein, we hypothesized that sirtinol might act on cellular pathways similar to that affected by these compounds. Using the human prostate cancer cell LNCaP as a model system, we found that sirtinol treatment led to concentration-dependent effects on multiple pathways. Sirtinol inhibited LNCaP cell growth and cell cycle. This growth inhibitory effect of sirtinol was due in part to alterations in the cellular pathways in which the hormones androgen, estrogen, and insulin-like growth factor-1 function. We also found that sirtinol induced Phase I and II detoxification enzymes in LNCaP cells. Sirtinol acted at a concentration of 25 microM, which is lower than that needed to inactivate sirtuin. Based on these results we reasoned that sirtinol exerted multiple effects in cells and the biological effects of sirtinol may not be due solely to inhibition of sirtuin. This work provided novel information for cancer researchers regarding a commonly used inhibitor of enzymes involved in prostate cancer prevention, and served as a basis for better design of future studies to understand the mechanism by which chemicals in plants act in the prevention of prostate cancer.
Technical Abstract: Sirtinol, a purported specific inhibitor of the nicotinamide adenine dinucleotide (NAD)-dependent type III histone deacetylase (also known as sirtuin), has been used extensively to identify chemopreventive/chemotherapeutic agents that modulate the activity of this group of enzymes. However, the molecular effect of sirtinol other than serving as sirtuin inhibitor in cells is less clear. The present study addressed this deficiency in the literature. Based on structural similarity with plant-derived cancer preventive/therapeutic compounds such as 3’, 3’-diindolylmethane, resveratrol and genistein, we hypothesized that sirtinol may act on pathways similar to that affected by these compounds in the human prostate cancer cell LNCaP. We found that sirtinol treatment of LNCaP cells led to concentration-dependent effects on multiple pathways. Sirtinol inhibited LNCaP cell cycle and growth that was correlated with up-regulation of cyclin inhibitor 1A mRNA. This effect may due to modulation of androgen, estrogen, and insulin like growth factor-1 mediated pathways as sirtinol treatment led to inhibition of mRNA expression of marker genes involved in these pathways. We also found sirtinol induced Phase I and II enzymes in LNCaP cells. The effects of sirtinol were observed at 25 microM, a concentration lower than KI for sirtuin activity. Based on these results, we reasoned that sirtinol exerted pleiotropic effects in cells and that its biological effects were not due solely to inhibition of sirtuin.