A Naphthoquinone Derivative, Shikonin, Has Insulin-Like Actions by Inhibiting Both Phosphatase and Tensin Homolog Deleted on Chromosome 10 and Tyrosine Phosphatases

Nigorikawa, Kiyomi; Yoshikawa, K; Sasaki, Tomo; Iida, Eiji; Tsukamoto, Mariko; Murakami, H.; Maehama, Tomohiko; Hazeki, Kaoru; Hazeki, Osamu

doi:10.1124/mol.106.025809

Cited by 34 publications

(24 citation statements)

References 37 publications

(42 reference statements)

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“…Whether these analogues can also modulate STAT3 activation is not clear. Unlike plumbagin, shikonin (49) and compound 5 (50), that are analogues of vitamin K, are know to inhibit protein tyrosine phosphates. Thus it is possible that not all analogues of vitamin K exhibit similar effects on STAT3 activation.…”

Section: Discussionmentioning

confidence: 99%

5-Hydroxy-2-Methyl-1,4-Naphthoquinone, a Vitamin K3 Analogue, Suppresses STAT3 Activation Pathway through Induction of Protein Tyrosine Phosphatase, SHP-1: Potential Role in Chemosensitization

Sandur

Pandey

Sung

et al. 2010

Molecular Cancer Research

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The activation of signal transducers and activators of transcription 3 (STAT3) has been linked with carcinogenesis through survival, proliferation, and angiogenesis of tumor cells. Agents that can suppress STAT3 activation have potential not only for prevention but also for treatment of cancer. In the present report, we investigated whether 5-hydroxy-2-methyl-1,4-naphthoquinone (plumbagin), an analogue of vitamin K, and isolated from chitrak (Plumbago zeylanica), an Ayurvedic medicinal plant, can modulate the STAT3 pathway. We found that plumbagin inhibited both constitutive and interleukin 6-inducible STAT3 phosphorylation in multiple myeloma (MM) cells and this correlated with the inhibition of c-Src, Janus-activated kinase (JAK)1, and JAK2 activation. Vanadate, however, reversed the plumbagin-induced downregulation of STAT3 activation, suggesting the involvement of a protein tyrosine phosphatase. Indeed, we found that plumbagin induced the expression of the protein tyrosine phosphatase, SHP-1, and silencing of the SHP-1 abolished the effect of plumbagin. This agent also downregulated the expression of STAT3-regulated cyclin D1, Bcl-xL, and vascular endothelial growth factor; activated caspase-3; induced poly (ADP ribose) polymerase cleavage; and increased the sub-G 1 population of MM cells. Consistent with these results, overexpression of constitutive active STAT3 significantly reduced the plumbagin-induced apoptosis. When compared with AG490, a rationally designed STAT3/JAK2 inhibitor, plumbagin was found more potent in suppressing the proliferation of cells. Plumbagin also significantly potentiated the apoptotic effects of thalidomide and bortezomib in MM cells. Overall, these results suggest that the plumbagin inhibits STAT3 activation pathway through the induction of SHP-1 and this may mediate the sensitization of STAT3 overexpressing cancers to chemotherapeutic agents.

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Section: Discussionmentioning

confidence: 99%

5-Hydroxy-2-Methyl-1,4-Naphthoquinone, a Vitamin K3 Analogue, Suppresses STAT3 Activation Pathway through Induction of Protein Tyrosine Phosphatase, SHP-1: Potential Role in Chemosensitization

Sandur

Pandey

Sung

et al. 2010

Molecular Cancer Research

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“…Previous studies have shown that shikonin increases glucose uptake in adipocytes independently of the insulin receptor, IRS proteins and PI3K but through an unidentified tyrosine kinase mediated mechanism requiring Akt phosphorylation [2]. In CHO cells transfected with the insulin receptor, shikonin inhibited PTEN which may explain some of its insulin like actions such as increased glucose uptake [5].…”

Section: Introductionmentioning

confidence: 93%

Shikonin Increases Glucose Uptake in Skeletal Muscle Cells and Improves Plasma Glucose Levels in Diabetic Goto-Kakizaki Rats

et al. 2011

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BackgroundThere is considerable interest in identifying compounds that can improve glucose homeostasis. Skeletal muscle, due to its large mass, is the principal organ for glucose disposal in the body and we have investigated here if shikonin, a naphthoquinone derived from the Chinese plant Lithospermum erythrorhizon, increases glucose uptake in skeletal muscle cells.Methodology/Principal FindingsShikonin increases glucose uptake in L6 skeletal muscle myotubes, but does not phosphorylate Akt, indicating that in skeletal muscle cells its effect is medaited via a pathway distinct from that used for insulin-stimulated uptake. Furthermore we find no evidence for the involvement of AMP-activated protein kinase in shikonin induced glucose uptake. Shikonin increases the intracellular levels of calcium in these cells and this increase is necessary for shikonin-mediated glucose uptake. Furthermore, we found that shikonin stimulated the translocation of GLUT4 from intracellular vesicles to the cell surface in L6 myoblasts. The beneficial effect of shikonin on glucose uptake was investigated in vivo by measuring plasma glucose levels and insulin sensitivity in spontaneously diabetic Goto-Kakizaki rats. Treatment with shikonin (10 mg/kg intraperitoneally) once daily for 4 days significantly decreased plasma glucose levels. In an insulin sensitivity test (s.c. injection of 0.5 U/kg insulin), plasma glucose levels were significantly lower in the shikonin-treated rats. In conclusion, shikonin increases glucose uptake in muscle cells via an insulin-independent pathway dependent on calcium.Conclusions/SignificanceShikonin increases glucose uptake in skeletal muscle cells via an insulin-independent pathway dependent on calcium. The beneficial effects of shikonin on glucose metabolism, both in vitro and in vivo, show that the compound possesses properties that make it of considerable interest for developing novel treatment of type 2 diabetes.

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“…1A), from the herb Lithospermum erythrorhizon, has been shown to possess numerous pharmacological properties, including anti-inflammatory and antitumor properties (Chen et al, 2002;Nakaya and Miyasaka, 2003). Shikonin has also been shown to have insulin-like actions through inhibition of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and tyrosine phosphatases (Nigorikawa et al, 2006). In our previous report, we identified shikonin to be a potent suppressor of TNF-␣ production (Staniforth et al, 2004).…”

mentioning

confidence: 99%

Inhibition of Tumor Necrosis Factor-α through Selective Blockade of Pre-mRNA Splicing by Shikonin

Chiu¹,

Yang²

2007

Mol Pharmacol

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We previously developed a gene-gun-based in vivo screening system and identified shikonin as a potent suppressor of tumor necrosis factor-␣ (TNF-␣) gene expression. Here, we show that shikonin selectively inhibits the expression of TNF-␣ at the RNA splicing level. Treatment of lipopolysaccharide-stimulated human primary monocytes and THP-1 cells with shikonin resulted in normal transcriptional induction of TNF-␣, but unspliced pre-mRNA accumulated at the expense of functional mRNA. This effect occurred with noncytotoxic doses of shikonin and was highly specific, because mRNA production of neither a housekeeping gene nor another inflammatory cytokine gene, interleukin-8 (IL-8), was affected. Moreover, cotreatment with lipopolysaccharide (LPS) and shikonin increased the endpoint protein production of IL-8, accompanied by suppressed activation of the double-stranded RNA-activated protein kinase (PKR) pathway. Because PKR inactivation has been shown to down-regulate the splicing process of TNF-␣ RNA and interfere with translation, our findings suggest that shikonin may achieve differential modulation of cytokine protein expression through inactivation of the PKR pathway and reveal that regulation of TNF-␣ pre-mRNA splicing may constitute a promising target for future anti-inflammatory application.Normal immune function is maintained by an elaborate balance between the activities of pro-and anti-inflammatory cytokines. One of the most important pro-inflammatory cytokines, TNF-␣, plays a pivotal role in immune and inflammatory responses (Aggarwal et al., 2001;Locksley et al., 2001). Inappropriate expression or overexpression of TNF-␣ can lead to the progression of inflammatory and autoimmune diseases (Locksley et al., 2001;Schottelius et al., 2004;Wood et al., 2006), and recent studies suggest that inhibition of TNF-␣ production is an appealing target for the development of novel anti-inflammatory drugs (Palladino et al., 2003).Expression of the "immediate-early" TNF-␣ gene is tightly controlled at several levels to ensure its silence in the absence of stimulation (Kontoyiannis et al., 1999) and enable a rapid response to noxious stimuli. Activator protein 1 and nuclear factor-B, the two major transcription factors regulating TNF-␣, are currently the primary targets for anti-TNF-␣ drug discovery (Aggarwal et al., 2001;Tsukagoshi et al., 2001), and they are also important in regulating the expression of many other immune-related genes.Shikonin (Fig. 1A), from the herb Lithospermum erythrorhizon, has been shown to possess numerous pharmacological properties, including anti-inflammatory and antitumor properties (Chen et al., 2002;Nakaya and Miyasaka, 2003). Shikonin has also been shown to have insulin-like actions through inhibition of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and tyrosine phosphatases (Nigorikawa et al., 2006). In our previous report, we identified shikonin to be a potent suppressor of TNF-␣ production (Staniforth et al., 2004). However, the mechanism through which shikoni...

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A Naphthoquinone Derivative, Shikonin, Has Insulin-Like Actions by Inhibiting Both Phosphatase and Tensin Homolog Deleted on Chromosome 10 and Tyrosine Phosphatases

Cited by 34 publications

References 37 publications

5-Hydroxy-2-Methyl-1,4-Naphthoquinone, a Vitamin K3 Analogue, Suppresses STAT3 Activation Pathway through Induction of Protein Tyrosine Phosphatase, SHP-1: Potential Role in Chemosensitization

5-Hydroxy-2-Methyl-1,4-Naphthoquinone, a Vitamin K3 Analogue, Suppresses STAT3 Activation Pathway through Induction of Protein Tyrosine Phosphatase, SHP-1: Potential Role in Chemosensitization

Shikonin Increases Glucose Uptake in Skeletal Muscle Cells and Improves Plasma Glucose Levels in Diabetic Goto-Kakizaki Rats

Inhibition of Tumor Necrosis Factor-α through Selective Blockade of Pre-mRNA Splicing by Shikonin

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