Enhancement of radiosensitivity by inhibition of c-Jun N-terminal kinase activity in a Lewis lung carcinoma-bearing subcutaneous tumor mouse model

Li, Chunhao; Lim, Sang Chul; Ryu, Hyang‐Hwa; Moon, Kyung‐Sub; Jung, Tae‐Young; Jung, Shin

doi:10.3892/or.2016.5204

Cited by 6 publications

(7 citation statements)

References 37 publications

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“…Increasing evidence supports the crucial roles of CDC25A, BCL2, and c-Jun in promoting the proliferation, apoptosis, and radioresistance of lung cancer cells [89][90][91][92][93]. Here, we provided further evidence that CLPT M1L induced radioresistance of NSCLC cells by coactivating ERβ and enhancing the expression of ERβ target genes.…”

Section: Discussionsupporting

confidence: 67%

CLPTM1L induces estrogen receptor β signaling-mediated radioresistance in non-small cell lung cancer cells

Chen

Jiang

et al. 2020

Cell Commun Signal

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Introduction Radioresistance is a major challenge in lung cancer radiotherapy, and new radiosensitizers are urgently needed. Estrogen receptor β (ERβ) is involved in the progression of non-small cell lung cancer (NSCLC), however, the role of ERβ in the response to radiotherapy in lung cancer remains elusive. In the present study, we investigated the mechanism underlying ERβ-mediated transcriptional activation and radioresistance of NSCLC cells. Methods Quantitative real-time PCR, western blot and immunohistochemistry were used to detect the expression of CLPTM1L, ERβ and other target genes. The mechanism of CLPTM1L in modulation of radiosensitivity was investigated by chromatin immunoprecipitation assay, luciferase reporter gene assay, immunofluorescence staining, confocal microscopy, coimmunoprecipitation and GST pull-down assays. The functional role of CLPTM1L was detected by function assays in vitro and in vivo. Results CLPTM1L expression was negatively correlated with the radiosensitivity of NSCLC cell lines, and irradiation upregulated CLPTM1L in radioresistant (A549) but not in radiosensitive (H460) NSCLC cells. Meanwhile, IR induced the translocation of CLPTM1L from the cytoplasm into the nucleus in NSCLC cells. Moreover, CLPTM1L induced radioresistance in NSCLC cells. iTRAQ-based analysis and cDNA microarray identified irradiation-related genes commonly targeted by CLPTM1L and ERβ, and CLPTM1L upregulated ERβ-induced genes CDC25A, c-Jun, and BCL2. Mechanistically, CLPTM1L coactivated ERβ by directly interacting with ERβ through the LXXLL NR (nuclear receptor)-binding motif. Functionally, ERβ silencing was sufficient to block CLPTM1L-enhanced radioresistance of NSCLC cells in vitro. CLPTM1L shRNA treatment in combination with irradiation significantly inhibited cancer cell growth in NSCLC xenograft tumors in vivo. Conclusions The present results indicate that CLPTM1L acts as a critical coactivator of ERβ to promote the transcription of its target genes and induce radioresistance of NSCLC cells, suggesting a new target for radiosensitization in NSCLC therapy.

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Section: Discussionsupporting

confidence: 67%

CLPTM1L induces estrogen receptor β signaling-mediated radioresistance in non-small cell lung cancer cells

Chen

Jiang

et al. 2020

Cell Commun Signal

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“…We have already revealed that SP600125 can increase the radiosensitivity in an irradiated subcutaneous tumor model. 17 The current study was intended for a LLC-cell bearing mouse brain tumor model, focusing on tumor specific delivery of HVSP-NP as a radiosensitizer. In these brain models, even though nanoparticles can be given by tail vein injection, this condition alone remains difficult for nanoparticles to be delivered into the brain because of the BBB.…”

Section: Discussionmentioning

confidence: 99%

“…Western blotting was conducted according to the protocol established in previous studies. 17,34,35 Briefly, harvested cells were lysed with RIPA buffer containing Tris-HCl (pH 7.5), 1% Triton X-100, 0.15 M NaCl, 0.5% sodium deoxycholate, and 2 mM EDTA (Bio-solution). Proteins extracted from whole cell lysates (30 μg) were subjected to electrophoresis using 10% SDS-polyacrylamide gel at 100 V for 2 hours and then transferred to PVDF membranes at 100 V for 1 hour on ice.…”

Section: Western Blotting and Immunohistochemistry (Ihc)mentioning

confidence: 99%

“…[13][14][15][16] In a recent study, we have demonstrated that by blocking JNK signaling using SP600125, γH2AX expression is decreased and apoptosis is increased in irradiated lung and breast cancer cells. 17 SP600125 can be utilized as a radiosensitizer. Small molecule inhibitors such as SP600125 have no specificity against cancer cells and can spread out in the whole body.…”

Section: Introductionmentioning

confidence: 99%

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<p>Enhancing Radiotherapeutic Effect With Nanoparticle-Mediated Radiosensitizer Delivery Guided By Focused Gamma Rays In Lewis Lung Carcinoma-Bearing Mouse Brain Tumor Models</p>

Lim

Jeong

et al. 2019

IJN

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Background: Targeting radiosensitizer-incorporated nanoparticles to a tumor could allow for less normal tissue toxicity with more efficient drug release, thus improving the efficacy and safety of radiation treatment. The aim of this study was to improve tumor-specific delivery and bioavailability of a nanoparticle-mediated radiosensitizer in mouse brain tumor models. Methods: A pH-sensitive nanoparticle, chitoPEGAcHIS, was conjugated to recombinant peptide HVGGSSV that could bind to tax-interaction protein 1 (TIP-1) as a radiation-inducible receptor. Then the c-Jun N-terminal kinase (JNK) inhibitor, SP600125 was incorporated into this copolymer to fabricate a HVGGSSV-chitoPEGAcHIS-SP600125 (HVSP-NP) nanoradiosensitizer. In vitro and in vivo radiation treatment were performed using a Gamma Knife unit. The tumor targetability of HVSP-NP was estimated by optical bioluminescence. Synergistic therapeutic effects of radiation treatment and HVSP-NP were investigated in Lewis lung carcinoma (LLC) cell-bearing mouse brain tumor models. Results: The SP600125 JNK inhibitor effectively reduced DNA damage repair to irradiated LLC cells. A pH sensitivity assay indicated that HVSP-NP swelled at acidic pH and increased in diameter, and its release rate gradually increased. Optical bioluminescence assay showed that radiation induced TIP-1 expression in mouse brain tumor and that the nanoradiosensitizer selectively targeted irradiated tumors. Radiation treatment with HVSP-NP induced greater apoptosis and significantly inhibited tumor growth compared to radiation alone. Conclusion: As a novel nanoradiosensitizer, HVSP-NP was found to be able to selectively target irradiated tumors and significantly increase tumor growth delay in LLC-bearing mouse brain tumor models. This research shows that delivering a pH-sensitive nanoradiosensitizer to a brain tumor in which TIP-1 is induced by radiation can result in improved radiosensitizer-release in an acidic microenvironment of tumor tissue and in created synergistic effects in radiation treatment.

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“…The development of a nontoxic and efficient radiosensitizer is necessary. Our previous study showed that blocking c-Jun-N-terminal kinase (JNK) signaling increased radiosensitivity and delayed tumor growth in vitro and in an in vivo mouse tumor model [1,2]. With the development of nanobiotechnology, and owing to their unique properties, nanoparticles have become widely explored in cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

Synergistic Effects of Radiotherapy With JNK Inhibitor-Incorporated Nanoparticle in an Intracranial Lewis Lung Carcinoma Mouse Models

Lim

Jeong

et al. 2023

IEEE Trans.on Nanobioscience

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Background: Radiosurgery has been recognized as a reasonable treatment for metastatic brain tumors. Increasing the radiosensitivity and synergistic effects are possible ways to improve the therapeutic efficacy of specific regions of tumors. c-Jun-N-terminal kinase (JNK) signaling regulates H2AX phosphorylation to repair radiation-induced DNA breakage. We previously showed that blocking JNK signaling influenced radiosensitivity in vitro and in an in vivo mouse tumor model.Drugs can be incorporated into nanoparticles to produce a slow-release effect. This study assessed JNK radiosensitivity following the slow release of the JNK inhibitor SP600125 from a poly (DLlactide-co-glycolide) (LGEsese) block copolymer in a brain tumor model. Materials and Methods: A LGEsese block copolymer was synthesized to fabricate SP600125incorporated nanoparticles by nanoprecipitation and dialysis methods. The chemical structure of the LGEsese block copolymer was confirmed by 1H nuclear magnetic resonance (NMR) spectroscopy. The physicochemical and morphological properties were observed by transmission electron microscopy (TEM) imaging and measured with particle size analyzer. The blood-brain barrier (BBB) permeability to the JNK inhibitor was estimated by BBBflammaTM 440-dye-labeled SP600125. The effects of the JNK inhibitor were investigated using SP600125-incorporated nanoparticles and by optical bioluminescence, magnetic resonance imaging (MRI), and a survival assay in a mouse brain tumor model for Lewis lung cancer (LLC)-Fluc cells. DNA damage was estimated by histone γH2AX expression and apoptosis was assessed by the immunohistochemical examination of cleaved caspase 3. Results: The SP600125-incorporated nanoparticles of the LGEsese block copolymer were spherical and released SP600125 continuously for 24h. The use of BBBflammaTM 440-dye-labeled SP600125 demonstrated the ability of SP600125 to cross the BBB. The blockade of JNK signaling with SP600125-incorporated nanoparticles significantly delayed mouse brain tumor growth and prolonged mouse survival after radiotherapy. γH2AX, which mediates DNA repair protein, was reduced and the apoptotic protein cleaved-caspase 3 was increased by the combination of radiation and SP600125-incorporated nanoparticles.

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Enhancement of radiosensitivity by inhibition of c-Jun N-terminal kinase activity in a Lewis lung carcinoma-bearing subcutaneous tumor mouse model

Cited by 6 publications

References 37 publications

CLPTM1L induces estrogen receptor β signaling-mediated radioresistance in non-small cell lung cancer cells

CLPTM1L induces estrogen receptor β signaling-mediated radioresistance in non-small cell lung cancer cells

<p>Enhancing Radiotherapeutic Effect With Nanoparticle-Mediated Radiosensitizer Delivery Guided By Focused Gamma Rays In Lewis Lung Carcinoma-Bearing Mouse Brain Tumor Models</p>

Synergistic Effects of Radiotherapy With JNK Inhibitor-Incorporated Nanoparticle in an Intracranial Lewis Lung Carcinoma Mouse Models

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