Disruption of Heat Shock Protein 90 (Hsp90)-Protein Kinase Cδ (PKCδ) Interaction by (−)-Maackiain Suppresses Histamine H1 Receptor Gene Transcription in HeLa Cells

Nariai, Yuki; Mizuguchi, Hiroyuki; Ogasawara, Takeyasu; Nagai, Hiroaki; Sasaki, Yohei; Okamoto, Y; Yoshimura, Yoshiyuki; Kitamura, Yoshiaki; Nemoto, Hisao; Takeda, Noriaki; Fukui, Hirokazu

doi:10.1074/jbc.m115.657023

Cited by 24 publications

(16 citation statements)

References 42 publications

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“…Maackiain (MK, Figure 1 ) has been isolated from the dried roots of Sophora flavescens Aiton. and has been reported to have multiple pharmacologic properties, such as the inhibitory activity on monoamine oxidase B [ 27 ] and anti-allergic [ 28 ], anti-cancer [ 29 ], and anti-inflammatory activities [ 30 ]. However, the effectiveness of MK against PD has not been evaluated.…”

Section: Introductionmentioning

confidence: 99%

Maackiain Ameliorates 6-Hydroxydopamine and SNCA Pathologies by Modulating the PINK1/Parkin Pathway in Models of Parkinson’s Disease in Caenorhabditis elegans and the SH-SY5Y Cell Line

Tsai

Liu

et al. 2020

IJMS

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The movement disorder Parkinson’s disease (PD) is the second most frequently diagnosed neurodegenerative disease, and is associated with aging, the environment, and genetic factors. The intracellular aggregation of α-synuclein and the loss of dopaminergic neurons in the substantia nigra pars compacta are the pathological hallmark of PD. At present, there is no successful treatment for PD. Maackiain (MK) is a flavonoid extracted from dried roots of Sophora flavescens Aiton. MK has emerged as a novel agent for PD treatment that acts by inhibiting monoamine oxidase B. In this study, we assessed the neuroprotective potential of MK in Caenorhabditis elegans and investigated possible mechanism of this neuroprotection in the human SH-SY5Y cell line. We found that MK significantly reduced dopaminergic neuron damage in 6-hydroxydopamine (6-OHDA)-exposed worms of the BZ555 strain, with corresponding improvements in food-sensing behavior and life-span. In transgenic worms of strain NL5901 treated with 0.25 mM MK, the accumulation of α-synuclein was diminished by 27% (p < 0.01) compared with that in untreated worms. Moreover, in worms and the SH-SY5Y cell line, we confirmed that the mechanism of MK-mediated protection against PD pathology may include blocking apoptosis, enhancing the ubiquitin-proteasome system, and augmenting autophagy by increasing PINK1/parkin expression. The use of small interfering RNA to downregulate parkin expression in vivo and in vitro could reverse the benefits of MK in PD models. MK may have considerable therapeutic applications in PD.

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Section: Introductionmentioning

confidence: 99%

Maackiain Ameliorates 6-Hydroxydopamine and SNCA Pathologies by Modulating the PINK1/Parkin Pathway in Models of Parkinson’s Disease in Caenorhabditis elegans and the SH-SY5Y Cell Line

Tsai

Liu

et al. 2020

IJMS

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“…We also reported that heat shock protein 90 (Hsp90) regulated PKCδ signaling in HeLa cells (24). Therefore, we investigated the effect of quercetin and Hsp90 inhibitors on PMA-induced glucagon secretion.…”

Section: Effect Of Quercetin On Glucagon Secretion From Isolated Isletsmentioning

confidence: 99%

Protein kinase C-δ signaling regulates glucagon secretion from pancreatic islets

et al. 2017

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: Accumulating evidence supports the "glucagonocentric hypothesis", in which antecedent α-cell failure and inhibition of glucagon secretion are responsible for diabetes progression. Protein kinase C (PKC) is involved in glucagon secretion from α-cells, although which PKC isozyme is involved and the mechanism underlying this PKC-regulated glucagon secretion remains unknown. Here, the involvement of PKCδ in the onset and progression of diabetes was elucidated. Immunofluorescence studies revealed that PKCδ was expressed and activated in α-cells of STZ-induced diabetic model mice. Phorbol 12-myristate 13-acetate (PMA) stimulation significantly augmented glucagon secretion from isolated islets. Pre-treatment with quercetin and rottlerin, PKCδ signaling inhibitors, significantly suppressed the PMA-induced elevation of glucagon secretion. While Go6976, a Ca 2+ -dependent PKC selective inhibitor did not suppress glucagon secretion. Quercetin suppressed PMA-induced phosphorylation of Tyr 311 of PKCδ in isolated islets. However, quercetin itself had no effect on either glucagon secretion or glucagon mRNA expression. Our data suggest that PKCδ signaling inhibitors suppressed glucagon secretion. Elucidation of detailed signaling pathways causing PKCδ activation in the onset and progression of diabetes followed by the augmentation of glucagon secretion could lead to the identification of novel therapeutic target molecules and the development of novel therapeutic drugs for diabetes.

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“…To investigate whether Y‐632 inhibited Hsp90 ATPase activity, we undertook a malachite green assay using recombinant full‐length yeast Hsp90. Considering the IC 50 values of Hsp90 inhibitors for Hsp90 ATPase activity are reported to be much higher than the concentrations that could induce degradation of Hsp90 client proteins in tumor cells, the concentration of Y‐632 we used in this assay was up to 500 μM. As shown in Figure (a), GA significantly abolished Hsp90 ATPase activity by 49% ( P < 0.05) and 95% ( P < 0.001) at 1 μM and 100 μM, respectively, but Y‐632 had no significant effect on Hsp90 ATPase activity.…”

Section: Resultsmentioning

confidence: 99%

Y‐632 inhibits heat shock protein 90 (Hsp90) function by disrupting the interaction between Hsp90 and Hsp70/Hsp90 organizing protein, and exerts antitumor activity in vitro and in vivo

et al. 2016

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Heat shock protein 90 (Hsp90) stabilizes a variety of proteins required for cancer cell survival and has been identified as a promising drug target for cancer treatment. To date, several Hsp90 inhibitors have entered into clinical trials, but none has been approved for cancer therapy yet. Thus, exploring new Hsp90 inhibitors with novel mechanisms of action is urgent. In the present study, we show that Y‐632, a novel pyrimidine derivative, inhibited Hsp90 in a different way from the conventional Hsp90 inhibitor geldanamycin. Y‐632 induced degradation of diverse Hsp90 client proteins through the ubiquitin–proteasome pathway, as geldanamycin did; however, it neither directly bound to Hsp90 nor inhibited Hsp90 ATPase activity. Y‐632 inhibited Hsp90 function mainly through inducing intracellular thiol oxidation, which led to disruption of the Hsp90–Hsp70/Hsp90 organizing protein complex and further induced cell adhesion inhibition, G0/G1 cell cycle arrest, and apoptosis. Moreover, Y‐632 efficiently overcame imatinib resistance mediated by Bcr‐Abl point mutations both in vitro and in vivo. We believe that Y‐632, acting as a novel small‐molecule inhibitor of the Hsp90–Hsp70/Hsp90 organizing protein complex, has great potential to be a promising Hsp90 inhibitor for cancer therapy, such as for imatinib‐resistant leukemia.

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Disruption of Heat Shock Protein 90 (Hsp90)-Protein Kinase Cδ (PKCδ) Interaction by (−)-Maackiain Suppresses Histamine H1 Receptor Gene Transcription in HeLa Cells

Cited by 24 publications

References 42 publications

Maackiain Ameliorates 6-Hydroxydopamine and SNCA Pathologies by Modulating the PINK1/Parkin Pathway in Models of Parkinson’s Disease in Caenorhabditis elegans and the SH-SY5Y Cell Line

Maackiain Ameliorates 6-Hydroxydopamine and SNCA Pathologies by Modulating the PINK1/Parkin Pathway in Models of Parkinson’s Disease in Caenorhabditis elegans and the SH-SY5Y Cell Line

Protein kinase C-δ signaling regulates glucagon secretion from pancreatic islets

Y‐632 inhibits heat shock protein 90 (Hsp90) function by disrupting the interaction between Hsp90 and Hsp70/Hsp90 organizing protein, and exerts antitumor activity in vitro and in vivo

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