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3-Deoxyschweinfurthin B Lowers Cholesterol Levels by Decreasing Synthesis and Increasing Export in Cultured Cancer Cell Lines

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Lipids

Abstract

The schweinfurthins have potent antiproliferative activity in multiple glioblastoma multiforme (GBM) cell lines; however, the mechanism by which growth is impeded is not fully understood. Previously, we demonstrated that the schweinfurthins reduce the level of key isoprenoid intermediates in the cholesterol biosynthetic pathway. Herein, we describe the effects of the schweinfurthins on cholesterol homeostasis. Intracellular cholesterol levels are greatly reduced in cells incubated with 3-deoxyschweinfurthin B (3dSB), an analog of the natural product schweinfurthin B. Decreased cholesterol levels are due to decreased cholesterol synthesis and increased cholesterol efflux; both of these cellular actions can be influenced by liver X-receptor (LXR) activation. The effects of 3dSB on ATP-binding cassette transporter 1 levels and other LXR targets are similar to that of 25-hydroxycholesterol, an LXR agonist. Unlike 25-hydroxycholesterol, 3dSB does not act as a direct agonist for LXR α or β. These data suggest that cholesterol homeostasis plays a significant role in the growth inhibitory activity of the schweinfurthins and may elucidate a mechanism that can be targeted in human cancers such as GBM.

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Abbreviations

3dSB:

3-Deoxyschweinfurthin B

LXR:

Liver X receptor

NCI60:

National Cancer Institute 60 cell cancer screen

CNS:

Central nervous system

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Financial Support Statement

This project was supported in part by the Roy J. Carver Charitable Trust, the Roland W. Holden Family Program for Experimental Therapeutics, and the National Institutes of Health (5R42NS069272).

Author information

Author notes

  1. Megan M. Weivoda

    Present address: Department of Endocrinology, Mayo Clinic, Rochester, MN, USA

  2. Jeffrey D. Neighbors

    Present address: Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA

  3. Raymond J. Hohl

    Present address: Departments of Medicine and Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA

Authors and Affiliations

  1. Department of Internal Medicine, University of Iowa, Iowa City, IA, 52242, USA

    Craig H. Kuder & Raymond J. Hohl

  2. Department of Pharmacology, University of Iowa, Iowa City, IA, 52242, USA

    Megan M. Weivoda, David F. Wiemer & Raymond J. Hohl

  3. Department of Chemistry, University of Iowa, Iowa City, IA, 52242, USA

    Jeffrey D. Neighbors & David F. Wiemer

  4. Department of Public Health Sciences, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA

    Ying Zhang & Junjia Zhu

  5. Mail Code CH72, 500 University Drive, Hershey, PA, 17033-0850, USA

    Raymond J. Hohl

Authors
  1. Craig H. Kuder
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  2. Megan M. Weivoda
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  3. Ying Zhang
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  4. Junjia Zhu
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  7. Raymond J. Hohl
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Corresponding author

Correspondence to Raymond J. Hohl.

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Kuder, C.H., Weivoda, M.M., Zhang, Y. et al. 3-Deoxyschweinfurthin B Lowers Cholesterol Levels by Decreasing Synthesis and Increasing Export in Cultured Cancer Cell Lines. Lipids 50, 1195–1207 (2015). https://doi.org/10.1007/s11745-015-4083-z

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  • DOI: https://doi.org/10.1007/s11745-015-4083-z

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