Protein kinase Cε interacts with Stat3 and regulates its activation that is essential for the development of skin cancer

Aziz, Moammir H.; Manoharan, Herbert T.; Sand, Jordan M.; Verma, Ajit Kumar

doi:10.1002/mc.20356

Cited by 53 publications

(57 citation statements)

References 45 publications

(119 reference statements)

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“…Our experiments showed that luteolin not only inhibited PKCε and c-Src kinase activity in vitro but also in vivo. PKCε is known to promote skin cancer development by inducing oncogenic signaling (16), and its crucial role in skin carcinogenesis is well characterized (17,41). c-Src was originally classified as a proto-oncogene (42,43) that plays a Figure 5.…”

Section: Discussionmentioning

confidence: 99%

Luteolin Inhibits Protein Kinase Cϵ and c-Src Activities and UVB-Induced Skin Cancer

et al. 2010

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Luteolin, a flavonoid present in various vegetables including onion and broccoli, has been reported to possess anticarcinogenic effects. However, its chemopreventive effect on UV-induced skin cancer and its mechanism are not fully understood. Herein, we examined the chemopreventive effect and associated mechanisms of luteolin in the JB6 P+ cell line and the SKH-1 hairless mouse model. Luteolin suppressed UVB-induced cyclooxygenase-2 expression and activator protein-1 and nuclear factor-κB activity in JB6 P+ cells. Immunoblot and kinase assay data showed that luteolin attenuated protein kinase Cε (PKCε) and Src kinase activities and subsequently inhibited UVB-induced phosphorylation of mitogen-activated protein kinases and the Akt signaling pathway. In addition, pull-down assays revealed that luteolin binds directly to PKCε and Src in an ATP-competitive manner. Importantly, luteolin suppressed tumor incidence, multiplicity, and overall size in SKH-1 hairless mice. Analysis of the skin by immunohistochemistry and immunoblotting showed that luteolintreated groups had a substantial reduction in the levels of cyclooxygenase-2, tumor necrosis factor-α, and proliferating cell nuclear antigen compared with groups treated with only UVB. Further analysis using skin lysates showed that luteolin inhibited PKCε and Src kinase activity. Together, these data suggest that luteolin exerts potent chemopreventive activity against UVB-induced skin cancer mainly by targeting PKCε and Src.

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Section: Discussionmentioning

confidence: 99%

Luteolin Inhibits Protein Kinase Cϵ and c-Src Activities and UVB-Induced Skin Cancer

et al. 2010

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“…Janus-activated kinase 1 activates STAT3 by phosphorylating at Ser-727 and at Tyr-705 (8,28,42,45). The cooperation of both serine and tyrosine phosphorylation is necessary for full activation of STAT3 (3,11). Activation of the AR N-terminal domain by interleukin-6 (IL-6) via STAT3 signal pathways has been reported (48).…”

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confidence: 99%

Hepatitis C Virus Core Protein Augments Androgen Receptor-Mediated Signaling

Kanda

Steele²,

Ray

2008

J Virol

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Hepatitis C virus (HCV) infection is frequently associated with the development of hepatocellular carcinoma (HCC), which is one of the male-dominant diseases. Androgen signaling in liver may be related to carcinogenesis. In this study, we investigated whether HCV proteins cross talk with the androgen receptor (AR) signaling pathway for promotion of carcinogenesis. We have demonstrated that HCV core protein alone or in context with other HCV proteins enhances AR-mediated transcriptional activity and further augments in the presence of androgen. Subsequent study suggested that HCV core protein activates STAT3, which in turn enhances AR-mediated transcription. This activity was blocked by a pharmacological inhibitor of the Jak/Stat signaling pathway, AG490. Vascular endothelial growth factor (VEGF) is a target gene of AR in liver and plays an important role in angiogenesis. Therefore, we examined whether HCV infection modulates VEGF expression in hepatocytes. Our results demonstrated that HCV enhances VEGF expression and facilitates tube formation in human coronary microvascular endothelial cells in the presence of AR. Together, our results suggest that HCV core protein acts as a positive regulator in AR signaling, providing further insight into oncogenic potential in the development of HCC in HCV-infected individuals.Hepatitis C virus (HCV) infection affects nearly 4 million people and is the most common cause of cirrhosis and hepatocellular carcinoma (HCC) in the United States (23). The current approved therapy for treatment for HCV is pegylated interferon in combination with ribavirin (43). Although several advances have shown promise for improving the management of HCV infection, it nevertheless remains as a major health problem (2, 7, 60). Regardless of the etiology, chronic liver diseases progress at unequal rates in the two sexes, with the major sequelae, such as cirrhosis and HCC, being more common in men than in women (16,54). The significance of androgen receptor (AR) expression in HCC and the surrounding liver has been studied extensively (18,31,33). With this background, we decided to investigate the relationship between AR and HCC after HCV infection, knowing that human liver expresses both estrogen receptors and ARs.AR is a ligand-dependent transcription factor that belongs to the nuclear receptor superfamily (14, 17). The transcriptional activation function of AR is not only essential for normal sexual development in men but is also implicated in the progression of cancer (9). AR has a modular structure containing the N terminus harboring transcriptional activation domain(s), a central DNA-binding domain, and a C-terminal ligand-binding domain. Binding of androgen to the ligand-binding domain induces conformational change in AR and leads to the shuttling of receptor from the cytoplasm to the nucleus, where it forms a homodimer and is recruited to the AR element (ARE). ARE is present in the regulatory elements on the target genes such as vascular endothelial growth factor (VEGF) and transforming growt...

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“…An increasing number of reports confirm that intracellular Ca 2ϩ regulates the transcription of several target genes (38,39). However, in this study we did not elucidate the mechanism by which intracellular Ca 2ϩ regulates IR expression.…”

Section: Discussionmentioning

confidence: 70%

Presenilin Regulates Insulin Signaling via a γ-Secretase-independent Mechanism

Maesako

Uemura

Kuzuya

et al. 2011

Journal of Biological Chemistry

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Presenilin (PS), a causative molecule of familial Alzheimer disease, acts as a crucial component of the ␥-secretase complex, which is required to cleave type I transmembrane proteins such as amyloid precursor protein and Notch. However, it also functions through ␥-secretase-independent pathways. Recent reports suggested that PS could regulate the expression level of cell surface receptors, including the PDGF and EGF receptors, followed by modulating their downstream pathways via ␥-secretase-independent mechanisms. The main purpose of this study was to clarify the effect of PS on expression of the insulin receptor (IR) as well as on insulin signaling. Here, we demonstrate that PS inhibited IR transcription and reduced IR expression, and this was followed by down-regulation of insulin signaling. Moreover, we suggest that neither ␥-secretase activity nor Wnt/ ␤-catenin signaling can reduce the expression of IR, but a PSmediated increase in the intracellular Ca 2؉ level can be associated with it. These results clearly indicate that PS can functionally regulate insulin signaling by controlling IR expression.

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Protein kinase Cε interacts with Stat3 and regulates its activation that is essential for the development of skin cancer

Cited by 53 publications

References 45 publications

Luteolin Inhibits Protein Kinase Cϵ and c-Src Activities and UVB-Induced Skin Cancer

Luteolin Inhibits Protein Kinase Cϵ and c-Src Activities and UVB-Induced Skin Cancer

Hepatitis C Virus Core Protein Augments Androgen Receptor-Mediated Signaling

Presenilin Regulates Insulin Signaling via a γ-Secretase-independent Mechanism

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