Natural Iminosugar (+)-Lentiginosine Inhibits ATPase and Chaperone Activity of Hsp90

Piaz, Fabrizio Dal; Vassallo, Antonio; Chini, Maria Giovanna; Cordero, Franca M.; Cardona, Francesca; Pisano, Claudio; Bifulco, Giuseppe; Tommasi, Nunziatina De; Brandi, Alberto

doi:10.1371/journal.pone.0043316

Cited by 44 publications

(26 citation statements)

References 41 publications

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“…Information on putative binding site and mode of interaction between HEWL and vitamin k3 was obtained from molecular docking using Autodock 4.2 program45. Molecular docking results are summarises in supplementary Figure S1 and supplementary Table 2.…”

Section: Resultsmentioning

confidence: 99%

Vitamin k3 inhibits protein aggregation: Implication in the treatment of amyloid diseases

Alam

Chaturvedi

Siddiqi

et al. 2016

Sci Rep

154

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Protein misfolding and aggregation have been associated with several human diseases such as Alzheimer’s, Parkinson’s and familial amyloid polyneuropathy etc. In this study, anti-fibrillation activity of vitamin k3 and its effect on the kinetics of amyloid formation of hen egg white lysozyme (HEWL) and Aβ-42 peptide were investigated. Here, in combination with Thioflavin T (ThT) fluorescence assay, circular dichroism (CD), transmission electron microscopy and cell cytotoxicity assay, we demonstrated that vitamin k3 significantly inhibits fibril formation as well as the inhibitory effect is dose dependent manner. Our experimental studies inferred that vitamin k3 exert its neuro protective effect against amyloid induced cytotoxicity through concerted pathway, modifying the aggregation formation towards formation of nontoxic aggregates. Molecular docking demonstrated that vitamin k3 mediated inhibition of HEWL and Aβ-42 fibrillogenesis may be initiated by interacting with proteolytic resistant and aggregation prone regions respectively. This work would provide an insight into the mechanism of protein aggregation inhibition by vitamin k3; pave the way for discovery of other small molecules that may exert similar effect against amyloid formation and its associated neurodegenerative diseases.

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Section: Resultsmentioning

confidence: 99%

Vitamin k3 inhibits protein aggregation: Implication in the treatment of amyloid diseases

Alam

Chaturvedi

Siddiqi

et al. 2016

Sci Rep

154

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“…SPR studies were performed using an optical biosensor BIACORE 3000 (GE Healthcare, Milano, Italy) employing established methods. [38][39][40] Briefly, recombinant human LXR alpha protein was immobilized on a CM5 sensor chip using a 5 μM solution in sodium acetate 50 mM, pH 4.5 at a flow rate of 5 μl/min using standard amine-coupling protocols to obtain densities of 8-12 kRU. The carboxylic groups of the chip were previously activated by EDC 0.…”

Section: Surface Plasmon Resonance (Spr) Analysesmentioning

confidence: 99%

Binding of polyunsaturated fatty acids to LXRα and modulation of SREBP‐1 interaction with a specific SCD1 promoter element

Caputo

Rosa

Rescigno

et al. 2014

Cell Biochemistry & Function

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Stearoyl-CoA desaturase 1 (SCD1) is the rate limiting enzyme in unsaturated fatty acid biosynthesis. This enzyme has an important role in the regulation of hepatic lipogenesis and lipid oxidation, and alterations in these pathways may lead to several diseases. We examined, in HepG2 cell cultures, the mechanism of SCD1 regulation considering the involvement of two transcription factors: liver X receptor alpha (LXRα) and sterol regulatory element-binding protein-1 (SREBP-1), also investigating the effect of dietary polyunsaturated fatty acids (PUFAs) on this process. The analysis of SCD1 promoter allowed to identify a functional SREBP-1 binding site (SRE 1). LXRα activation increased SCD1 protein level through upregulation of SREBP-1 and its consequent binding to SRE 1 sequence. Polyunsaturated docosahexaenoic acid (DHA, C22:6), eicosapentaenoic acid (EPA, C20:5) and arachidonic acid (AA, C20:4) were able to reduce SREBP-1 binding to SCD1 promoter, while saturated stearic acid (SA, C18:0) did not give any effect. Surface plasmon resonance analysis showed a direct binding of DHA, EPA and AA to LXRα. These data indicate a direct inhibitory interaction of PUFAs with LXRα, a consequent reduction of SREBP-1 and of its binding to SCD1 promoter. This information provides a mechanism to explain the regulation of lipogenic pathways induced by PUFAs.

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“…This failure uncovers the need to discover novel Hsp90 inhibitors based on diverse chemical skeletons and with superior chemotherapeutic properties for cancer treatment. Recently, several plant−derived small molecules have been discovered exhibiting inhibitory activity towards Hsp90, such as epigallocatechin gallate [13], gedunin [14], lentiginosine [15], celastrol [3] and deguelin [16].…”

Section: Introductionmentioning

confidence: 99%

Identification of the Plant Compound Geraniin as a Novel Hsp90 Inhibitor

et al. 2013

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Besides its function in normal cellular growth, the molecular chaperone heat shock protein 90 (Hsp90) binds to a large number of client proteins required for promoting cancer cell growth and/or survival. In an effort to discover new small molecules able to inhibit the Hsp90 ATPase and chaperoning activities, we screened, by a surface plasmon resonance assay, a small library including different plant polyphenols. The ellagitannin geraniin, was identified as the most promising molecule, showing a binding affinity to Hsp90α similar to that of 17-(allylamino)-17-demethoxygeldanamycin (17AGG). Geraniin was able to inhibit in vitro the Hsp90α ATPase activity in a dose−dependent manner, with an inhibitory efficiency comparable to that measured for 17-AAG. In addition, this compound compromised the chaperone activity of Hsp90α, monitored by the citrate synthase thermal induced aggregation assay. Geraniin decreased the viability of HeLa and Jurkat cell lines and caused an arrest in G2/M phase. We also proved that following exposure to different concentrations of geraniin, the level of expression of the client proteins c-Raf, pAkt, and EGFR was strongly down−regulated in both the cell lines. These results, along with the finding that geraniin did not exert any appreciable cytotoxicity on normal cells, encourage further studies on this compound as a promising chemical scaffold for the design of new Hsp90 inhibitors.

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Natural Iminosugar (+)-Lentiginosine Inhibits ATPase and Chaperone Activity of Hsp90

Cited by 44 publications

References 41 publications

Vitamin k3 inhibits protein aggregation: Implication in the treatment of amyloid diseases

Vitamin k3 inhibits protein aggregation: Implication in the treatment of amyloid diseases

Binding of polyunsaturated fatty acids to LXRα and modulation of SREBP‐1 interaction with a specific SCD1 promoter element

Identification of the Plant Compound Geraniin as a Novel Hsp90 Inhibitor

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