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Piperlongumine inhibits lung tumor growth via inhibition of nuclear factor kappa B signaling pathway.

ABSTRACT: Piperlongumine has anti-cancer activity in numerous cancer cell lines via various signaling pathways. But there has been no study regarding the mechanisms of PL on the lung cancer yet. Thus, we evaluated the anti-cancer effects and possible mechanisms of PL on non-small cell lung cancer (NSCLC) cells in vivo and in vitro. Our findings showed that PL induced apoptotic cell death and suppressed the DNA binding activity of NF-?B in a concentration dependent manner (0-15??M) in NSCLC cells. Docking model and pull down assay showed that PL directly binds to the DNA binding site of nuclear factor-?B (NF-?B) p50 subunit, and surface plasmon resonance (SPR) analysis showed that PL binds to p50 concentration-dependently. Moreover, co-treatment of PL with NF-?B inhibitor phenylarsine oxide (0.1??M) or p50 siRNA (100?nM) augmented PL-induced inhibitory effect on cell growth and activation of Fas and DR4. Notably, co-treatment of PL with p50 mutant plasmid (C62S) partially abolished PL-induced cell growth inhibition and decreased the enhanced expression of Fas and DR4. In xenograft mice model, PL (2.5-5 mg/kg) suppressed tumor growth of NSCLC dose-dependently. Therefore, these results indicated that PL could inhibit lung cancer cell growth via inhibition of NF-?B signaling pathway in vitro and in vivo.

SUBMITTER: Zheng J

PROVIDER: S-EPMC4873819 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Piperlongumine inhibits lung tumor growth via inhibition of nuclear factor kappa B signaling pathway.

Zheng Jie J Son Dong Ju DJ Gu Sun Mi SM Woo Ju Rang JR Ham Young Wan YW Lee Hee Pom HP Kim Wun Jae WJ Jung Jae Kyung JK Hong Jin Tae JT

Scientific reports 20160520

Piperlongumine has anti-cancer activity in numerous cancer cell lines via various signaling pathways. But there has been no study regarding the mechanisms of PL on the lung cancer yet. Thus, we evaluated the anti-cancer effects and possible mechanisms of PL on non-small cell lung cancer (NSCLC) cells in vivo and in vitro. Our findings showed that PL induced apoptotic cell death and suppressed the DNA binding activity of NF-κB in a concentration dependent manner (0-15 μM) in NSCLC cells. Docking ...[more]

PMID: 27198178

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Project description:Human Immunodeficiency Virus-1 (HIV-1)-associated neurocognitive disorder (HAND) is likely neuroinflammatory in origin, believed to be triggered by inflammatory and oxidative stress responses to cytokines and HIV protein gene products such as the HIV transactivator of transcription (Tat). Here we demonstrate increased messenger RNA for nuclear factor-kappa B (NF-kappaB) family member, transcription factor RelB, in the brain of doxycycline-induced Tat transgenic mice, and increased RelB synthesis in Tat-exposed microglial cells. Since genetic ablation of RelB in mice leads to multi-organ inflammation, we hypothesized that Tat-induced, newly synthesized RelB inhibits cytokine production by microglial cells, possibly through the formation of transcriptionally inactive RelB/RelA complexes. Indeed, tumor necrosis factor-alpha (TNFalpha) production in monocytes isolated from RelB deficient mice was significantly higher than in monocytes isolated from RelB expressing controls. Moreover, RelB overexpression in microglial cells inhibited Tat-induced TNFalpha synthesis in a manner that involved transcriptional repression of the TNFalpha promoter, and increased phosphorylation of RelA at serine 276, a prerequisite for increased RelB/RelA protein interactions. The Rel-homology-domain within RelB was necessary for this interaction. Overexpression of RelA itself, in turn, significantly increased TNFalpha promoter activity, an effect that was completely blocked by RelB overexpression. We conclude that RelB regulates TNFalpha cytokine synthesis by competitive interference binding with RelA, which leads to downregulation of TNFalpha production. Moreover, because Tat activates both RelB and TNFalpha in microglia, and because Tat induces inflammatory TNFalpha synthesis via NF-kappaB, we posit that RelB serves as a cryoprotective, anti-inflammatory, counter-regulatory mechanism for pathogenic NF-kappaB activation. These findings identify a novel regulatory pathway for controlling HIV-induced microglial activation and cytokine production that may have important therapeutic implications for the management of HAND.

Project description:BACKGROUND: Medulloblastoma is a highly malignant pediatric brain tumor that requires surgery, whole brain and spine irradiation, and intense chemotherapy for treatment. A more sophisticated understanding of the pathophysiology of medulloblastoma is needed to successfully reduce the intensity of treatment and improve outcomes. Nuclear factor kappa-B (NF?B) is a signaling pathway that controls transcriptional activation of genes important for tight regulation of many cellular processes and is aberrantly expressed in many types of cancer. METHODS: To test the importance of NF?B to medulloblastoma cell growth, the effects of multiple drugs that inhibit NF?B, pyrrolidine dithiocarbamate, diethyldithiocarbamate, sulfasalazine, curcumin and bortezomib, were studied in medulloblastoma cell lines compared to a malignant glioma cell line and normal neurons. Expression of endogenous NF?B was investigated in cultured cells, xenograft flank tumors, and primary human tumor samples. A dominant negative construct for the endogenous inhibitor of NF?B, I?B, was prepared from medulloblastoma cell lines and flank tumors were established to allow specific pathway inhibition. RESULTS: We report high constitutive activity of the canonical NF?B pathway, as seen by Western analysis of the NF?B subunit p65, in medulloblastoma tumors compared to normal brain. The p65 subunit of NF?B is extremely highly expressed in xenograft tumors from human medulloblastoma cell lines; though, conversely, the same cells in culture have minimal expression without specific stimulation. We demonstrate that pharmacological inhibition of NF?B in cell lines halts proliferation and leads to apoptosis. We show by immunohistochemical stain that phosphorylated p65 is found in the majority of primary tumor cells examined. Finally, expression of a dominant negative form of the endogenous inhibitor of NF?B, dnI?B, resulted in poor xenograft tumor growth, with average tumor volumes 40% smaller than controls. CONCLUSIONS: These data collectively demonstrate that NF?B signaling is important for medulloblastoma tumor growth, and that inhibition can reduce tumor size and viability in vivo. We discuss the implications of NF?B signaling on the approach to managing patients with medulloblastoma in order to improve clinical outcomes.

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Piperlongumine inhibits lung tumor growth via inhibition of nuclear factor kappa B signaling pathway.

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Piperlongumine inhibits lung tumor growth via inhibition of nuclear factor kappa B signaling pathway.

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