Cathepsin L activated by mutant p53 and Egr-1 promotes ionizing radiation-induced EMT in human NSCLC

Wang, Wenjuan; Xiong, Yajie; Ding, Xinyuan; Wang, Long; Zhao, Yifan; Yao, Fei; Zhu, Ying; Shen, Xuan; Tan, Chunyan; Liang, Zhong‐Qin

doi:10.1186/s13046-019-1054-x

Cited by 42 publications

(27 citation statements)

References 44 publications

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“…This would suggest that, in parasitized DCs, migratory responses are maintained while activation is suppressed or down-modulated (Figure 9). In line with this, recent reports show that Egr-1 responses promote epithelial-mesenchymal transition (EMT) and metastasis in malignancies (Shao et al, 2018; Wang et al, 2019). T. gondii encounters DCs in peripheral tissues, such as the intestine, and DCs function as shuttles (“Trojan horse”) that potentiate the systemic dissemination of the parasite (Courret et al, 2006; Lambert et al, 2006; Bierly et al, 2008).…”

Section: Discussionmentioning

confidence: 58%

Sustained Egr-1 Response via p38 MAP Kinase Signaling Modulates Early Immune Responses of Dendritic Cells Parasitized by Toxoplasma gondii

Hoeve

Hakimi

Barragán

2019

Front. Cell. Infect. Microbiol.

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As a response to a diverse array of external stimuli, early growth response protein 1 (Egr-1) plays important roles in the transcriptional regulation of inflammation and the cellular immune response. However, a number of intracellular pathogens colonize immune cells and the implication of Egr-1 in the host-pathogen interplay has remained elusive. Here, we have characterized the Egr-1 responses of primary murine and human dendritic cells (DCs) upon challenge with the obligate intracellular parasite Toxoplasma gondii. We report that live intracellular parasites induce a sustained high expression of Egr-1 in DCs, different from the immediate-early Egr-1 response to parasite lysates, inactivated parasites or LPS. Moreover, a distinct nuclear localization of elevated amounts of Egr-1 protein was detected in infected DCs, but not in by-stander DCs. The ERK1/2 MAPK signaling pathway mediated the canonical immediate-early Egr-1 response to soluble antigens in a MyD88/TLR-dependent fashion. In contrast, a non-canonical extended Egr-1 response that relied primarily on p38 MAPK signaling was induced by intracellular parasites and was exhibited similarly by MyD88-deficient and wildtype DCs. The extended phase Egr-1 response was dramatically reduced upon challenge of DCs with T. gondii parasites deficient in GRA24, a secreted p38-interacting protein. Further, Egr-1-silenced primary DCs maintained their migratory responses upon T. gondii challenge. Importantly, Egr-1 silencing led to elevated expression of co-stimulatory molecules (CD40, CD80) in Toxoplasma-infected DCs and in LPS-challenged immature DCs, indicating that Egr-1 responses suppressed maturation of DCs. Moreover, the IL-12 and IL-2 responses of Toxoplasma-challenged DCs were modulated in a GRA24-dependent fashion. Jointly, the data show that the Egr-1 responses of DCs to microbial external stimuli and intracellular stimuli can be selectively mediated by ERK1/2 or p38 MAPK signaling, and that Egr-1 can act as an intrinsic negative modulator of maturation in primary DCs.

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Section: Discussionmentioning

confidence: 58%

Sustained Egr-1 Response via p38 MAP Kinase Signaling Modulates Early Immune Responses of Dendritic Cells Parasitized by Toxoplasma gondii

Hoeve

Hakimi

Barragán

2019

Front. Cell. Infect. Microbiol.

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“…The transcription factor p53 is known to control radiation sensitivity [25,26,27,28]. Except in a few reports, p53 dysfunction has been shown to correlate with reduced radiosensitivity.…”

Section: Resultsmentioning

confidence: 99%

Deficiency of 15-LOX-1 Induces Radioresistance through Downregulation of MacroH2A2 in Colorectal Cancer

Kim

et al. 2019

Cancers

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Despite the importance of radiation therapy, there are few radiation-related markers available for use in clinical practice. A larger catalog of such biomarkers is required to help clinicians decide when radiotherapy should be replaced with a patient-specific treatment. Arachidonate 15-lipoxygenase (15-LOX-1) enzyme is involved in polyunsaturated fatty acid metabolism. When colorectal cancer (CRC) cells were exposed to radiation, 15-LOX-1 was upregulated. To verify whether 15-LOX-1 protects against or induces DNA damage, we irradiated sh15-LOX-1 stable cells. We found that low 15-LOX-1 is correlated with radioresistance in CRC cells. These data suggest that the presence of 15-LOX-1 can be used as a marker for radiation-induced DNA damage. Consistent with this observation, gene-set-enrichment analysis based on microarray experiments showed that UV_RESPONSE was decreased in sh15-LOX-1 cells compared to shCon cells. Moreover, we discovered that the expression of the histone H2A variant macroH2A2 was sevenfold lower in sh15-LOX-1 cells. Overall, our findings present mechanistic evidence that macroH2A2 is transcriptionally regulated by 15-LOX-1 and suppresses the DNA damage response in irradiated cells by delaying H2AX activation.

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“…As a member of the early gene family, Egr-1 has an important role in drug resistance in cancer cells and could regulate the expression of CTSL [24–27]. Previous studies in our laboratory have indicated that Egr-1 may be the target protein of mut-p53 in regulating CTSL mediated EMT under IR in NSCLC [40]. We indicated here that Egr-1 regulated CTSL-mediated cisplatin resistance in lung cancer by affecting the activity of CTSL promoter.…”

Section: Discussionmentioning

confidence: 99%

Cathepsin L-mediated resistance of paclitaxel and cisplatin is mediated by distinct regulatory mechanisms

Zhao

Zhu

Wang

et al. 2019

J Exp Clin Cancer Res

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Background Cathepsin L (CTSL) is a cysteine protease known to have important roles in regulating cancer cellular resistance to chemotherapy. However mechanism underlying which regulates CTSL-mediated drug resistance remain largely unknown. Methods We used NSCLC cell lines: A549, A549/TAX (paclitaxel-resistant), A549/DDP (cisplatin-resistant), H460 and PC9 cells, to evaluate CTSL and drug resistance changes. Tumor specimens from 53 patients with NSCLC and Xenograft models was also utilized to explore the regulatory relationship of CTSL, TGF-β, Egr-1 and CREB. Results TGF-β and smad3 were overexpressed only in A549/TAX cells, silencing TGF-β or smad3 in A549/TAX cells decreased the expression of CTSL and enhanced their sensitivity to paclitaxel. Smad3 binds to the Smad-binding-element(SBE) of the CTSL promoter, resulting in increased activity of the CTSL promoter and subsequent CTSL. Egr-1 and CREB were overexpressed only in A549/DDP cells, and silencing Egr-1 or CREB reduced the expression of CTSL and increased cisplatin cytotoxicity. CREB could affect the activity of the CTSL promoter by binding to it. And the potential regulatory factors of CTSL were consistent in vivo and in human lung cancer. These different regulatory mechanisms of CTSL-mediated drug resistance exist in two other NSCLC cell lines. Conclusion CTSL-mediated drug resistance to paclitaxel and cisplatin may be modulated by different mechanisms. The results of our study identified different mechanisms regulating CTSL-mediated drug resistance and identified smad3 as a novel regulator of CTSL. Electronic supplementary material The online version of this article (10.1186/s13046-019-1299-4) contains supplementary material, which is available to authorized users.

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Cathepsin L activated by mutant p53 and Egr-1 promotes ionizing radiation-induced EMT in human NSCLC

Cited by 42 publications

References 44 publications

Sustained Egr-1 Response via p38 MAP Kinase Signaling Modulates Early Immune Responses of Dendritic Cells Parasitized by Toxoplasma gondii

Sustained Egr-1 Response via p38 MAP Kinase Signaling Modulates Early Immune Responses of Dendritic Cells Parasitized by Toxoplasma gondii

Deficiency of 15-LOX-1 Induces Radioresistance through Downregulation of MacroH2A2 in Colorectal Cancer

Cathepsin L-mediated resistance of paclitaxel and cisplatin is mediated by distinct regulatory mechanisms

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