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Geranylgeranylacetone selectively binds to the HSP70 of Helicobacter pylori and alters its coccoid morphology.

Grave E, Yokota S, Yamamoto S, Tamura A, Ohtaki-Mizoguchi T, Yokota K, Oguma K, Fujiwara K, Ogawa N, Okamoto T, Otaka M, Itoh H - Sci Rep (2015)

Bottom Line: GGA-treated cells elicited enhanced interleukin-8 production by gastric cancer cell lines and potentiated susceptibility to complement as compared to untreated cells.This morphological conversion by GGA resulted in accelerated growth of H. pylori.These results suggest a model in which GGA sensitizes H. pylori to antibiotic treatment by converting the cells to an actively growing state.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Science, Graduate School and Faculty of Engineering Science, Akita University, Akita 010-8502, Japan.

ABSTRACT
Geranylgeranylacetone (GGA) is used to treat patients suffering from peptic ulcers and gastritis. We examined the effect of GGA on Helicobacter pylori, which is a causative factor of gastrointestinal diseases. Previously, we have reported that GGA binds specifically to the molecular chaperone HSP70. In this paper, we report that GGA bounds to H. pylori HSP70 (product of the DnaK gene) with 26-times higher affinity than to human HSP70, and induced large conformational changes as observed from surface plasmon resonance and circular dichroism. Binding of GGA suppressed the activity of the H. pylori chaperone. GGA also altered several characteristics of H. pylori cells. GGA-treated cells elicited enhanced interleukin-8 production by gastric cancer cell lines and potentiated susceptibility to complement as compared to untreated cells. GGA also caused morphological alterations in H. pylori as reflected in fewer coccoid-like cells, suggesting that GGA converts H. pylori to an actively dividing, spiral state (vegetative form) from a non-growing, coccoid state. This morphological conversion by GGA resulted in accelerated growth of H. pylori. These results suggest a model in which GGA sensitizes H. pylori to antibiotic treatment by converting the cells to an actively growing state.

No MeSH data available.


Related in: MedlinePlus

Effect of GGA on the chaperone activity of DnaK and HSP70.(A) time course of 50 μM DnaK (closed black diamond), 0.25 μM citrate synthase (CS) aggregation in buffer (closed red square), buffer containing 50 μM DnaK (closed yellow triangle), buffer containing 50 μM DnaK and 0.5 mM GGA (closed purple circle), buffer containing 50 μM DnaK and 2.5 mM GGA (closed blue circle), and buffer containing 50 μM DnaK and 5.0 mM GGA (closed green circle). (B) time course of 50 μM HSP70 (closed black diamond), 0.5 M citrate synthase aggregation in buffer (closed red square), buffer containing 50 μM HSP70 (closed yellow triangle), buffer containing 50 μM HSP70 and 0.5 mM GGA (closed purple circle), buffer containing 50 μM HSP70 and 2.5 mM GGA (closed blue circle), and buffer containing 50 μM HSP70 and 5.0 mM GGA (closed green circle).
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f4: Effect of GGA on the chaperone activity of DnaK and HSP70.(A) time course of 50 μM DnaK (closed black diamond), 0.25 μM citrate synthase (CS) aggregation in buffer (closed red square), buffer containing 50 μM DnaK (closed yellow triangle), buffer containing 50 μM DnaK and 0.5 mM GGA (closed purple circle), buffer containing 50 μM DnaK and 2.5 mM GGA (closed blue circle), and buffer containing 50 μM DnaK and 5.0 mM GGA (closed green circle). (B) time course of 50 μM HSP70 (closed black diamond), 0.5 M citrate synthase aggregation in buffer (closed red square), buffer containing 50 μM HSP70 (closed yellow triangle), buffer containing 50 μM HSP70 and 0.5 mM GGA (closed purple circle), buffer containing 50 μM HSP70 and 2.5 mM GGA (closed blue circle), and buffer containing 50 μM HSP70 and 5.0 mM GGA (closed green circle).

Mentions: We compared the effect of GGA on the chaperone activities of DnaK and HSP70. Citrate synthase (CS) is very unstable to heat (see Fig. 4 for the thermal aggregation assay). Both DnaK (Fig. 4A) and HSP70 (Fig. 4B) inhibited CS aggregation completely. GGA had only slight effect on chaperone activity of HSP70 (Fig. 4B). HSP70 activity was reduced by only 15% at 5 mM GGA; and reduced by 10 and 5% 2.5 and 0.5 mM, respectively. In contrast, the chaperone activity of DnaK was inhibited almost completely at GGA 5 mM (Fig. 4A). These results are consistent with the influence of the drug on the conformations of the two proteins.


Geranylgeranylacetone selectively binds to the HSP70 of Helicobacter pylori and alters its coccoid morphology.

Grave E, Yokota S, Yamamoto S, Tamura A, Ohtaki-Mizoguchi T, Yokota K, Oguma K, Fujiwara K, Ogawa N, Okamoto T, Otaka M, Itoh H - Sci Rep (2015)

Effect of GGA on the chaperone activity of DnaK and HSP70.(A) time course of 50 μM DnaK (closed black diamond), 0.25 μM citrate synthase (CS) aggregation in buffer (closed red square), buffer containing 50 μM DnaK (closed yellow triangle), buffer containing 50 μM DnaK and 0.5 mM GGA (closed purple circle), buffer containing 50 μM DnaK and 2.5 mM GGA (closed blue circle), and buffer containing 50 μM DnaK and 5.0 mM GGA (closed green circle). (B) time course of 50 μM HSP70 (closed black diamond), 0.5 M citrate synthase aggregation in buffer (closed red square), buffer containing 50 μM HSP70 (closed yellow triangle), buffer containing 50 μM HSP70 and 0.5 mM GGA (closed purple circle), buffer containing 50 μM HSP70 and 2.5 mM GGA (closed blue circle), and buffer containing 50 μM HSP70 and 5.0 mM GGA (closed green circle).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4561889&req=5

f4: Effect of GGA on the chaperone activity of DnaK and HSP70.(A) time course of 50 μM DnaK (closed black diamond), 0.25 μM citrate synthase (CS) aggregation in buffer (closed red square), buffer containing 50 μM DnaK (closed yellow triangle), buffer containing 50 μM DnaK and 0.5 mM GGA (closed purple circle), buffer containing 50 μM DnaK and 2.5 mM GGA (closed blue circle), and buffer containing 50 μM DnaK and 5.0 mM GGA (closed green circle). (B) time course of 50 μM HSP70 (closed black diamond), 0.5 M citrate synthase aggregation in buffer (closed red square), buffer containing 50 μM HSP70 (closed yellow triangle), buffer containing 50 μM HSP70 and 0.5 mM GGA (closed purple circle), buffer containing 50 μM HSP70 and 2.5 mM GGA (closed blue circle), and buffer containing 50 μM HSP70 and 5.0 mM GGA (closed green circle).
Mentions: We compared the effect of GGA on the chaperone activities of DnaK and HSP70. Citrate synthase (CS) is very unstable to heat (see Fig. 4 for the thermal aggregation assay). Both DnaK (Fig. 4A) and HSP70 (Fig. 4B) inhibited CS aggregation completely. GGA had only slight effect on chaperone activity of HSP70 (Fig. 4B). HSP70 activity was reduced by only 15% at 5 mM GGA; and reduced by 10 and 5% 2.5 and 0.5 mM, respectively. In contrast, the chaperone activity of DnaK was inhibited almost completely at GGA 5 mM (Fig. 4A). These results are consistent with the influence of the drug on the conformations of the two proteins.

Bottom Line: GGA-treated cells elicited enhanced interleukin-8 production by gastric cancer cell lines and potentiated susceptibility to complement as compared to untreated cells.This morphological conversion by GGA resulted in accelerated growth of H. pylori.These results suggest a model in which GGA sensitizes H. pylori to antibiotic treatment by converting the cells to an actively growing state.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Science, Graduate School and Faculty of Engineering Science, Akita University, Akita 010-8502, Japan.

ABSTRACT
Geranylgeranylacetone (GGA) is used to treat patients suffering from peptic ulcers and gastritis. We examined the effect of GGA on Helicobacter pylori, which is a causative factor of gastrointestinal diseases. Previously, we have reported that GGA binds specifically to the molecular chaperone HSP70. In this paper, we report that GGA bounds to H. pylori HSP70 (product of the DnaK gene) with 26-times higher affinity than to human HSP70, and induced large conformational changes as observed from surface plasmon resonance and circular dichroism. Binding of GGA suppressed the activity of the H. pylori chaperone. GGA also altered several characteristics of H. pylori cells. GGA-treated cells elicited enhanced interleukin-8 production by gastric cancer cell lines and potentiated susceptibility to complement as compared to untreated cells. GGA also caused morphological alterations in H. pylori as reflected in fewer coccoid-like cells, suggesting that GGA converts H. pylori to an actively dividing, spiral state (vegetative form) from a non-growing, coccoid state. This morphological conversion by GGA resulted in accelerated growth of H. pylori. These results suggest a model in which GGA sensitizes H. pylori to antibiotic treatment by converting the cells to an actively growing state.

No MeSH data available.


Related in: MedlinePlus