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HnRNPK inhibits GSK3? Ser9 phosphorylation, thereby stabilizing c-FLIP and contributes to TRAIL resistance in H1299 lung adenocarcinoma cells.

ABSTRACT: c-FLIP (cellular FLICE-inhibitory protein) is the pivotal regulator of TRAIL resistance in cancer cells, It is a short-lived protein degraded through the ubiquitin/proteasome pathway. The discovery of factors and mechanisms regulating its protein stability is important for the comprehension of TRAIL resistance by tumor cells. In this study, we show that, when H1299 lung adenocarcinoma cells are treated with TRAIL, hnRNPK is translocated from nucleus to cytoplasm where it interacts and co-localizes with GSK3?. We find that hnRNPK is able to inhibit the Ser9 phosphorylation of GSK3? by PKC. This has the effect of activating GSK3? and thereby stabilizing c-FLIP protein which contributes to the resistance to TRAIL in H1299 cells. Our immunohistochemical analysis using tissue microarray provides the clinical evidence of this finding by establishing a negative correlation between the level of hnRNPK expression and the Ser9 phosphorylation of GSK3? in both lung adenocarcinoma tissues and normal tissues. Moreover, in all cancer tissues examined, hnRNPK was found in the cytoplasm whereas it is exclusively nuclear in the normal tissues. Our study sheds new insights on the molecular mechanisms governing the resistance to TRAIL in tumor cells, and provides new clues for the combinatorial chemotherapeutic interventions with TRAIL.

SUBMITTER: Gao X

PROVIDER: S-EPMC4789638 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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hnRNPK inhibits GSK3β Ser9 phosphorylation, thereby stabilizing c-FLIP and contributes to TRAIL resistance in H1299 lung adenocarcinoma cells.

Gao Xuejuan X Feng Junxia J He Yujiao Y Xu Fengmei F Fan Xiaoqin X Huang Wensi W Xiong Haiting H Liu Qiuyu Q Liu Wanting W Liu Xiaohui X Sun Xuesong X He Qing-Yu QY Zhang Qihao Q Liu Langxia L

Scientific reports 20160314

c-FLIP (cellular FLICE-inhibitory protein) is the pivotal regulator of TRAIL resistance in cancer cells, It is a short-lived protein degraded through the ubiquitin/proteasome pathway. The discovery of factors and mechanisms regulating its protein stability is important for the comprehension of TRAIL resistance by tumor cells. In this study, we show that, when H1299 lung adenocarcinoma cells are treated with TRAIL, hnRNPK is translocated from nucleus to cytoplasm where it interacts and co-localiz ...[more]

PMID: 26972480

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Project description:Microglia-mediated neuroinflammation plays a crucial role in the pathophysiological process of multiple neurological disorders such as ischemic stroke, yet lacks effective therapeutic agents. Previously, we discovered one novel synthetic compound, tanshinol borneol ester (DBZ), possesses anti-inflammatory and anti-atherosclerotic activities, whereas little is known about its effects in CNS. Therefore, the present study aims to explore the effects and potential mechanism of DBZ on neuroinflammation and microglial function. Our studies revealed that DBZ significantly inhibited NF-κB activity, suppressed the production of pro-inflammatory mediators meanwhile promoted M2 mediators expression in LPS-stimulated BV2 cells and mouse primary microglia cells. DBZ also exhibited antioxidant activity by enhancing Nrf2 nuclear accumulation and transcriptional activity, increasing HO-1 and NQO1 expression, and inhibiting LPS-induced ROS generation in BV2 cells. Importantly, the anti-neuroinflammatory and antioxidant effects of DBZ above were reversed by Nrf2 knockdown. Additionally, DBZ ameliorated sickness behaviors of neuroinflammatory mice induced by systemic LPS administration, and significantly reduced infract volume, improved sensorimotor and cognitive function in rats subjected to transient middle cerebral artery occlusion (tMCAO); besides, DBZ restored microglia morphological alterations and shifted the M1/M2 polarization in both murine models. Mechanistically, DBZ-induced Nrf2 nuclear accumulation and antioxidant enzymes expression were accompanied by increased level of p-Akt(Ser473) (activation) and p-GSK3β(Ser9) (inactivation), and decreased nuclear level of Fyn both in vitro and in vivo. Pharmacologically inhibiting PI3K or activating GSK3β markedly increased nuclear density of Fyn in microglia cells, which blocked the promoting effect of DBZ on Nrf2 nuclear accumulation and its antioxidant and anti-neuroinflammatory activities. Collectively, these results indicated the effects of DBZ on microglia-mediated neuroinflammation were strongly associated with the nuclear accumulation and stabilization of Nrf2 via the Akt(Ser473)/GSK3β(Ser9)/Fyn pathway. With anti-neuroinflammatory and antioxidant properties, DBZ could be a promising new drug candidate for prevention and/or treatment of cerebral ischemia and other neuroinflammatory disorders.

Dataset Information

HnRNPK inhibits GSK3? Ser9 phosphorylation, thereby stabilizing c-FLIP and contributes to TRAIL resistance in H1299 lung adenocarcinoma cells.

Publications

hnRNPK inhibits GSK3β Ser9 phosphorylation, thereby stabilizing c-FLIP and contributes to TRAIL resistance in H1299 lung adenocarcinoma cells.

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