3-Deoxyschweinfurthin B Lowers Cholesterol Levels by Decreasing Synthesis and Increasing Export in Cultured Cancer Cell Lines.
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.
Department of Internal Medicine, University of Iowa, Iowa City, IA, 52242, USA.
Craig H
CH
Kuder
Department of Pharmacology, University of Iowa, Iowa City, IA, 52242, USA.|Department of Endocrinology, Mayo Clinic, Rochester, MN, USA.
Megan M
MM
Weivoda
Department of Public Health Sciences, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA.
Ying
Y
Zhang
Department of Public Health Sciences, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA.
Junjia
J
Zhu
Department of Chemistry, University of Iowa, Iowa City, IA, 52242, USA.|Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA.
Jeffrey D
JD
Neighbors
Department of Pharmacology, University of Iowa, Iowa City, IA, 52242, USA.|Department of Chemistry, University of Iowa, Iowa City, IA, 52242, USA.
David F
DF
Wiemer
Department of Internal Medicine, University of Iowa, Iowa City, IA, 52242, USA. rhohl@hmc.psu.edu.|Department of Pharmacology, University of Iowa, Iowa City, IA, 52242, USA. rhohl@hmc.psu.edu.|, Mail Code CH72, 500 University Drive, Hershey, PA, 17033-0850, USA. rhohl@hmc.psu.edu.|Departments of Medicine and Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA. rhohl@hmc.psu.edu.
Raymond J
RJ
Hohl
D064286:ATP Binding Cassette Transporter 1 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism; D005982:Glutathione Transferase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006888:Hydroxycholesterols / Q000378:metabolism; D006900:Hydroxylation; D007700:Kinetics; D000071518:Liver X Receptors; D009363:Neoplasm Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000819:agonists* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000924:Anticholesteremic Agents; D000972:Antineoplastic Agents, Phytogenic; D006888:Hydroxycholesterols; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D009363:Neoplasm Proteins; D057093:Orphan Nuclear Receptors; D011993:Recombinant Fusion Proteins; D013267:Stilbenes; C117233:schweinfurthin B; C007997:25-hydroxycholesterol; D002784:Cholesterol; D005982:Glutathione Transferase
Cancer; Cholesterol; Cholesterol metabolism; Metabolism; Nuclear receptors (LXR, PPAR, RXR); Oxysterols; Physiology; Specific lipids