PDK1 is a potential therapeutic target against angiosarcoma cells

Wada, Makoto; Horinaka, Mano; Yasuda, Shusuke; Masuzawa, Mikio; Sakai, Toshiyuki; Katoh, Norito

doi:10.1016/j.jdermsci.2015.01.015

Cited by 28 publications

(22 citation statements)

References 21 publications

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“…Phosphoinositide‐dependent protein kinase‐1 (PDK1) is a member of the atypical glandular cell AGC kinase subfamily that regulates the activities of most atypical glandular cell kinases during different development stages and treatment of cancers . PDK1 is proved to be a potential therapeutic target against angiosarcoma cells and is required in the leucine‐induced stimulation of the cardiac mammalian target of rapamycin (mTOR)/p70 ribosomal S6 kinase (p70S6K) pathway . Currently, it is widely reported that phosphatidylinositol 3‐kinase (PI3K)/Akt/mTOR signaling pathway acts as an essential pathway in the regulation of cell autophagy and apoptosis .…”

Section: Introductionmentioning

confidence: 99%

Retracted: microRNA‐145‐3p inhibits non‐small cell lung cancer cell migration and invasion by targeting PDK1 via the mTOR signaling pathway

Chen¹,

Zheng

Cai

et al. 2017

J of Cellular Biochemistry

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The mammalian target of rapamycin (mTOR) pathway is dysregulated in more than 50% of all human malignancies and is a major target in cancer treatment. In this study, we explored the underlying mechanism involving microRNA-145-3p (miR-145-3p) in the development and progression of non-small cell lung cancer (NSCLC) by targeting PDK1 via the mTOR signaling pathway. NSCLC tissues and adjacent normal tissues were obtained from 83 NSCLC patients. miR-145-3p, PDK1, and mTOR levels were determined by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry. Human NSCLC cell lines A549 and H1299 were transfected with miR-145-3p and siPDK1 to confirm the effect of miR-145-3p and PDK1 on NSCLC cells in vitro. Cell growth was evaluated by a CCK8 assay. Cell motility and chemotaxis analysis were determined by the scratch test and chemotaxis assay, respectively. The protein levels of PDK1 and mTOR were measured using the western blotting. Results showed lower level of miR-145-3p and higher levels of PDK1 and mTOR in NSCLC tissues compared to the adjacent normal tissues. In vitro results showed that cell growth, cell motility, and chemotaxis were all inhibited in cells transfected with miR-145-3p and those transfected with siPDK. Additionally, dual luciferase reporter gene assay helped confirmed that PDK1 is a target of miR-145. Finally, levels of PDK1, mTOR, and phosphorylated-mTOR were lower in cells transfected with miR-145-3p as well as those with siPDK1. These findings indicate that miR-145-3p may inhibit cell growth, motility, and chemotaxis in NSCLC by targeting PDK1 through suppressing the mTOR pathway. K E Y W O R D SmicroRNA-145-3p, mTOR pathway, non-small cell lung cancer, PDK1

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Section: Introductionmentioning

confidence: 99%

Retracted: microRNA‐145‐3p inhibits non‐small cell lung cancer cell migration and invasion by targeting PDK1 via the mTOR signaling pathway

Chen¹,

Zheng

Cai

et al. 2017

J of Cellular Biochemistry

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“…PDK1 plays important roles in mediating cellular responses such as cell growth, apoptosis, and angiogenesis [50][51][52][53][54][55]. Dysregulated activation of PI3K-PDK1-Akt is common in cancer, and different inhibitors are being developed to block the downstream effectors of this pathway [38,50,[56][57][58]. In our prior studies, we extensively characterized the PDK1 inhibitor BX-795, including its effects on aggregation at different doses and to various agonists such as collagen and AYPGKF [29].…”

Section: Discussionmentioning

confidence: 99%

PDK1 governs thromboxane generation and thrombosis in platelets by regulating activation of Raf1 in the MAPK pathway

Manne

Münzer

Badolia

et al. 2018

Journal of Thrombosis and Haemostasis

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Background Platelets are dynamic effector cells with functions that span hemostatic, thrombotic and inflammatory continua. Phosphoinositide-dependent protein kinase 1 (PDK1) regulates protease-activated receptor 4-induced platelet activation and thrombus formation through glycogen synthase kinase3β. However, whether PDK1 also signals through the ADP receptor and its functional importance in vivo remain unknown. Objective To establish the mechanism of PDK1 in ADP-induced platelet activation and thrombosis. Methods We assessed the role of PDK1 on 2MeSADP-induced platelet activation by measuring aggregation, thromboxane generation and phosphorylation events in the presence of BX-795, which inhibits PDK1, or by using platelet-specific PDK1 knockout mice and performing western blot analysis. PDK1 function in thrombus formation was assessed with an in vivo pulmonary embolism model. Results PDK1 inhibition with BX-795 reduced 2-methylthio-ADP (2MeSADP)-induced aggregation of human and murine platelets by abolishing thromboxane generation. Similar results were observed in pdk1 mice. PDK1 was also necessary for the phosphorylation of mitogen-activated protein kinase kinase 1/2 (MEK1/2), extracellular signal-regulated kinase 1/2, and cytosolic phospholipase A2, indicating that PDK1 regulates an upstream kinase in the mitogen-activated protein kinase (MAPK) pathway. We next determined that this upstream kinase is Raf-1, a serine/threonine kinase that is necessary for the phosphorylation of MEK1/2, as pharmacological inhibition and genetic ablation of PDK1 were sufficient to prevent Raf1 phosphorylation. Furthermore, in vivo inhibition or genetic ablation of PDK1 protected mice from collagen/epinephrine-induced pulmonary embolism. Conclusion PDK1 governs thromboxane generation and thrombosis in platelets that are stimulated with 2MeSADP by regulating activation of the MAPK pathway.

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“…Hyperactivation of PDK1 was identified in several types of human cancer (10)(11)(12). Downregulation of PDK1 inhibits metastasis of human breast cancer cells (12).…”

Section: Introductionmentioning

confidence: 99%

PDK1‑WNK1 signaling is affected by HBx and involved in the viability and metastasis of hepatic cells

Liu

Cong

et al. 2018

Oncol Lett

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Abstract. Hepatitis B virus (HBV)-encoded X antigen (HBx) contributes to the development of hepatocellular carcinoma (HCC). Although HBx has been implicated in the progression of HCC, its precise function in HBV-associated HCC remains unclear. In the present study, HBx affected 3-phosphoinositide-dependent protein kinase-1 (PDK1) and with-no-lysine (K) kinase (WNK1) signaling, which was identified to be involved in the viability and metastasis of hepatic cells. The phosphorylation of WNK1 was decreased when the hepatic cells were treated with a PDK1 inhibitor. The inhibition of PDK1 activity inhibited the viability and migration of hepatic cells. To the best of our knowledge, the present study is the first to identify the activation of PDK1 in HCC tissues, confirmed using western blot analysis. PDK1-WNK1 signaling may be a potential therapeutic target in HBV-associated liver cancer.

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PDK1 is a potential therapeutic target against angiosarcoma cells

Cited by 28 publications

References 21 publications

Retracted: microRNA‐145‐3p inhibits non‐small cell lung cancer cell migration and invasion by targeting PDK1 via the mTOR signaling pathway

Retracted: microRNA‐145‐3p inhibits non‐small cell lung cancer cell migration and invasion by targeting PDK1 via the mTOR signaling pathway

PDK1 governs thromboxane generation and thrombosis in platelets by regulating activation of Raf1 in the MAPK pathway

PDK1‑WNK1 signaling is affected by HBx and involved in the viability and metastasis of hepatic cells

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