The regulatory domain of protein kinase C delta positively regulates insulin receptor signaling

Jacob, Avi; Horovitz-Fried, Miriam; Aga-Mizrachi, Shlomit; Brutman-Barazani, Tamar; Okhrimenko, Hana; Zick, Yehiel; Brodie, Chaya; Sampson, Sanford R.

doi:10.1677/jme-09-0119

Cited by 10 publications

(15 citation statements)

References 56 publications

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“…Figure 5(A,B and C)shows that lanatoside C treatment downregulated the AKT/mTOR signaling pathway. Consistent with previous reports that PKCδ can positively or negatively regulate AKT activity depending on cell type and conditions4445, we further demonstrated a role for AKT in PKCδ-mediated HCC cell apoptosis. In our study, rotterlin and siPKCδ clearly reversed lanatoside C-induced decreases in the expression of AKT/mTOR signaling proteins (Fig.…”

Section: Discussionsupporting

confidence: 92%

Lanatoside C, a cardiac glycoside, acts through protein kinase Cδ to cause apoptosis of human hepatocellular carcinoma cells

Chao

Chen

Huang

et al. 2017

Sci Rep

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Recent studies have revealed that cardiac glycosides, such as digitalis and digoxin, have anticancer activity and may serve as lead compounds for the development of cancer treatments. The poor prognosis of hepatocellular carcinoma (HCC) patients reflects the development of resistance to current chemotherapeutic agents, highlighting the need for discovering new small-molecule therapeutics. Here, we found that lanatoside C, an anti-arrhythmic agent extracted from Digitalis lanata, inhibited the growth of HCC cells and dramatically decreased tumor volume as well as delayed tumor growth without obvious body weight loss. Moreover, lanatoside C triggered mitochondrial membrane potential (MMP) loss, activation of caspases and translocation of apoptosis-inducing factor (AIF) into the nucleus, which suggests that lanatoside C induced apoptosis through both caspase-dependent and -independent pathways. Furthermore, we discovered that lanatoside C activated protein kinase delta (PKCδ) via Thr505 phosphorylation and subsequent membrane translocation. Inhibition of PKCδ reversed lanatoside C-induced MMP loss and apoptosis, confirming that lanatoside C caused apoptosis through PKCδ activation. We also found that the AKT/mTOR pathway was negatively regulated by lanatoside C through PKCδ activation. In conclusion, we provide the first demonstration that the anticancer effects of lanatoside C are mainly attributable to PKCδ activation.

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Section: Discussionsupporting

confidence: 92%

Lanatoside C, a cardiac glycoside, acts through protein kinase Cδ to cause apoptosis of human hepatocellular carcinoma cells

Chao

Chen

Huang

et al. 2017

Sci Rep

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“…PKCδ has been shown to modify glucose uptake in myotubes (34), lipogenesis in liver (12), development of ER stress in hepatoma cells (19), and development of vascular changes in the retina (35). A role of PKCδ in the regulation of insulin secretion has also been reported in two studies using PKCδ transgenic mouse models (36,37), but the results of the latter were conflicting as to the direction of change.…”

Section: Discussionmentioning

confidence: 99%

“…Insulin also increases the amount of PKCδ within the nuclear fraction of L6 myotubes. Finally, some studies suggest that insulin can induce PKCδ activation through Src tyrosine kinase, and that PKCδ plays a positive role in insulin-stimulated glucose transport (34,(48)(49)(50). Whatever the exact mechanisms involved in these potentially positive roles of PKCδ, our results indicate that the major effect of high PKCδ is inhibition of insulin action in vivo and that deletion of PKCδ will improve insulin action and steatosis in liver and lead to an overall improvement in glucose tolerance and increase in whole body insulin sensitivity, as demonstrated by the euglycemic-hyperinsulinemic clamp.…”

Section: Discussionmentioning

confidence: 99%

PKCδ regulates hepatic insulin sensitivity and hepatosteatosis in mice and humans

Bézy¹,

Tran²,

et al. 2011

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C57BL/6J and 129S6/Sv (B6 and 129) mice differ dramatically in their susceptibility to developing diabetes in response to diet-or genetically induced insulin resistance. A major locus contributing to this difference has been mapped to a region on mouse chromosome 14 that contains the gene encoding PKCδ. Here, we found that PKCδ expression in liver was 2-fold higher in B6 versus 129 mice from birth and was further increased in B6 but not 129 mice in response to a high-fat diet. PRKCD gene expression was also elevated in obese humans and was positively correlated with fasting glucose and circulating triglycerides. Mice with global or liverspecific inactivation of the Prkcd gene displayed increased hepatic insulin signaling and reduced expression of gluconeogenic and lipogenic enzymes. This resulted in increased insulin-induced suppression of hepatic gluconeogenesis, improved glucose tolerance, and reduced hepatosteatosis with aging. Conversely, mice with liver-specific overexpression of PKCδ developed hepatic insulin resistance characterized by decreased insulin signaling, enhanced lipogenic gene expression, and hepatosteatosis. Therefore, changes in the expression and regulation of PKCδ between strains of mice and in obese humans play an important role in the genetic risk of hepatic insulin resistance, glucose intolerance, and hepatosteatosis; and thus PKCδ may be a potential target in the treatment of metabolic syndrome. IntroductionObesity and type 2 diabetes (T2D) are major health problems worldwide and are projected to further increase in prevalence over the next two decades. Likewise, the closely related metabolic syndrome, with all of its complications, is increasing at epidemic rates. Indeed, nonalcoholic hepatosteatosis is now the second most common cause of chronic liver failure (1). All these disorders are the result of interactions between inherited genetic factors and varying environmental exposures.Mouse models provide a powerful tool to investigate genetic and environmental components involved in the disease susceptibility. In mice, it has been shown that different genetic backgrounds strongly modify the susceptibility to diet-induced obesity, insulin resistance, hepatic steatosis, β cell failure, and T2D, in some cases in very dramatic ways (2-6). For example, we have previously shown that C57BL/6J and 129S6/Sv (B6 and 129) mice have remarkably different metabolic responses to high-fat diet-induced (HFD-induced) insulin resistance. On regular chow diet, B6 mice gain more weight, have higher levels of insulin and leptin, and show greater glucose intolerance than 129 mice, and these phenotypic differences are further exacerbated with high-fat feeding (6). Likewise, when stressed with genetically induced insulin resistance due to heterozygous deletion of both insulin receptor and insulin receptor substrate 1 (IRS-1), more than 90% of B6 mice develop diabetes, whereas less than 5% of 129 mice carrying this form of genetic insulin resistance become diabetic (5). This difference in development of diabete...

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“…Western blots were performed as described [Horovitz-Fried et al, 2006a;Jacob et al, 2010]. Equal protein loading of Western blots was confirmed by immunoblotting for b-actin.…”

Section: Western Blot Analysismentioning

confidence: 99%

Protein kinase Cδ but not PKCα is involved in insulin‐induced glucose metabolism in hepatocytes

Brutman-Barazani

Horovitz-Fried

Aga-Mizrachi

et al. 2012

J of Cellular Biochemistry

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The liver is a major insulin-responsive tissue responsible for glucose regulation. One important mechanism in this phenomenon is insulin-induced glycogen synthesis. Studies in our laboratory have shown that protein kinase Cs delta (PKCδ) and alpha (α) have important roles in insulin-induced glucose transport in skeletal muscle, and that their expression and activity are regulated by insulin. Their importance in glucose regulation in liver cells is unclear. In this study we investigated the possibility that these isoforms are involved in the mediation of insulin-induced glycogen synthesis in hepatocytes. Studies were done on rat hepatocytes in primary culture and on the AML-12 (alpha mouse liver) cell line. Insulin increased activity and tyrosine phosphorylation of PKCδ within 5 min. In contrast, activity and tyrosine phosphorylation of PKCα were not increased by insulin. PKCδ was constitutively associated with IR, and this was increased by insulin stimulation. Suppression of PKCδ expression by transfection with RNAi, or overexpression of kinase dead (dominant negative) PKCδ reduced both the insulin-induced activation of PKB/Akt and the phosphorylation of glycogen synthase kinase 3 (GSK3) and reduced significantly insulin-induced glucose uptake. In addition, treatment of primary rat hepatocytes with rottlerin abrogated insulin-induced increase in glycogen synthesis. Neither overexpression nor inhibition of PKCα appeared to alter activation of PKB, phosphorylation of GSK3 or glucose uptake in response to insulin. We conclude that PKCδ, but not PKCα, plays an essential role in insulin-induced glucose uptake and glycogenesis in hepatocytes.

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The regulatory domain of protein kinase C delta positively regulates insulin receptor signaling

Cited by 10 publications

References 56 publications

Lanatoside C, a cardiac glycoside, acts through protein kinase Cδ to cause apoptosis of human hepatocellular carcinoma cells

Lanatoside C, a cardiac glycoside, acts through protein kinase Cδ to cause apoptosis of human hepatocellular carcinoma cells

PKCδ regulates hepatic insulin sensitivity and hepatosteatosis in mice and humans

Protein kinase Cδ but not PKCα is involved in insulin‐induced glucose metabolism in hepatocytes

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