Abstract
BackgroundTGF-β is a key modulator in the regulation of cell proliferation and migration, and is also involved in the process of cancer development and progression. Previous studies have indicated that TGF-β responsiveness is determined by TGF-β receptor partitioning between lipid raft/caveolae-mediated and clathrin-mediated endocytosis. Lipid raft/caveolae-mediated endocytosis facilitates TGF-β degradation and thus suppressing TGF-β responsiveness. By contrast, clathrin-mediated endocytosis results in Smad2/3-dependent endosomal signaling, thereby promoting TGF-β responsiveness. Because betulinic acid shares a similar chemical structure with cholesterol and has been reported to insert into the plasma membrane, we speculate that betulinic acid changes the fluidity of the plasma membrane and modulates the signaling pathway associated with membrane microdomains. We propose that betulinic acid modulates TGF-β responsiveness by changing the partitioning of TGF-β receptor between lipid-raft/caveolae and non-caveolae microdomain on plasma membrane.MethodsWe employed sucrose-density gradient ultracentrifugation and confocal microscopy to determine membrane localization of TGF-β receptors and used a luciferase assay to examine the effects of betulinic acid in TGF-β-stimulated promoter activation. In addition, we perform western blotting to test TGF-β-induced Smad2 phosphorylation and fibronectin production.Results and conclusionsBetulinic acid induces translocation of TGF-β receptors from lipid raft/caveolae to non-caveolae microdomains without changing total level of TGF-β receptors. The betulinic acid-induced TGF-β receptors translocation is rapid and correlate with the TGF-β-induced PAI-1 reporter gene activation and growth inhibition in Mv1Lu cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s12929-016-0229-4) contains supplementary material, which is available to authorized users.
Highlights
transforming growth factor-beta (TGF-β) is a key modulator in the regulation of cell proliferation and migration, and is involved in the process of cancer development and progression
This study proposed that Betulinic acid (BetA) enhances TGF-β responsiveness by moving TGF-β receptors out of the lipid raft microdomain in the plasma membrane
To further assess whether BetA acts on ligand binding and subsequent active receptor complex formation or on downstream TGFβ signaling, Mv1Lu cells were transiently transfected with constitutively active ALK-5 (caALK-5), which resulted in an 8-fold induction of plasminogen activator inhibitor-1 (PAI-1) promoter activity without TGF-β stimulation (Fig. 3a)
Summary
TGF-β is a key modulator in the regulation of cell proliferation and migration, and is involved in the process of cancer development and progression. Previous studies have indicated that TGF-β responsiveness is determined by TGF-β receptor partitioning between lipid raft/caveolae-mediated and clathrin-mediated endocytosis. We propose that betulinic acid modulates TGF-β responsiveness by changing the partitioning of TGF-β receptor between lipid-raft/caveolae and non-caveolae microdomain on plasma membrane. Previous reports have indicated that BetA induces apoptosis in colorectal (DLD-1), breast (MCF7), prostate (PC-3), and lung (A549) cancer cells via the mitochondrial pathway [4,5,6]. Past studies have reported that BetA-induced apoptosis is not associated with the activation of ligand/receptor systems such as CD95, and does not involve p53 [1]. Recent studies have indicated that BetA modulate signaling through members of the TGF-β superfamily, which regulates inflammatory and immune responses, cell growth, differentiation, and apoptosis [9, 10]. The underlying mechanisms regarding the effects of BetA in TGF-β signaling are poorly understood
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