Targeting the Achilles’ heel of cancer cells via integrin-mediated delivery of ROS-generating dihydrolipoamide dehydrogenase

Dayan, Avraham; Fleminger, Gideon; Ashur‐Fabian, Osnat

doi:10.1038/s41388-019-0775-9

Cited by 32 publications

(36 citation statements)

References 49 publications

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“…3,4 Several biomarkers and therapeutic targets for OSCC have been demonstrated previously and may be useful for the diagnosis and prognosis of oral cancer in the future. [5][6][7][8][9] Therefore, efforts are still needed to develop effective targeted therapies for OSCC.…”

Section: Introductionmentioning

confidence: 99%

<p>Integrin α5/ITGA5 Promotes The Proliferation, Migration, Invasion And Progression Of Oral Squamous Carcinoma By Epithelial–Mesenchymal Transition</p>

Deng¹,

Wan²,

Yan³

2019

CMAR

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Background: Integrin signalling is involved in cell migration, invasion, proliferation and motility. Integrin α5/ITGA5 is a subunit of Integrin and contributes to the activation of Integrin signalling. The potential role of Integrin α5/ITGA5 in oral squamous cancer remains unknown. The aim of this study was to uncover the effect and mechanism of Integrin α5/ ITGA5 in the progression of oral squamous carcinoma. Method: TCGA database scanning, qRT-PCR, immunohistochemistry and Western blotting assays were used to detect the expression of Integrin α5/ITGA5 in tissues and cell lines. We established stable Integrin α5/ITGA5 overexpressing and Integrin α5/ITGA5 knockdown cell lines. We investigated the biological function and the underlying mechanism of Integrin α5/ ITGA5 through a series of experiments. Results: Integrin α5/ITGA5 was upregulated in cancer tissue, and its levels negatively correlated with the overall survival (OS) of patients. Integrin α5/ITGA5 promoted proliferation, migration and invasion in an oral squamous carcinoma cell line by EMT (epithelialmesenchymal transition). Conclusion: Integrin α5/ITGA5 promotes the proliferation, migration and invasion of oral squamous carcinoma.

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Section: Introductionmentioning

confidence: 99%

<p>Integrin α5/ITGA5 Promotes The Proliferation, Migration, Invasion And Progression Of Oral Squamous Carcinoma By Epithelial–Mesenchymal Transition</p>

Deng¹,

Wan²,

Yan³

2019

CMAR

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“…Mutations in the RAN gene likely play a critical role in pathology-related changes in miRNA transport and expression, and therefore, contribute to tumorigenesis and development [36]. DLD is associated with cysteine metabolism and regulation of ROS generation [37], and its role in tumor growth regulation mediated through the ferroptosis pathway in neck tumors has been investigated [38]. We observed that DLD and RAN regulate CLTRN expression in HCC cells by interacting with NRF1, and thereby affect ferroptosis and enhance the radiosensitivity of HCC cells.…”

Section: Discussionmentioning

confidence: 99%

CLTRN, Regulated by NRF1/RAN/DLD Protein Complex, Enhances Radiation Sensitivity of Hepatocellular Carcinoma Cells Through Ferroptosis Pathway

Yin

Cao

Zhou

et al. 2021

International Journal of Radiation Oncology*Biology*Physics

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Background Radiotherapy is a viable treatment option for patients with unresectable hepatocellular carcinoma (HCC). However, radiation resistance is an issue that needs to be addressed. In this context, cumulative evidence supports the functional roles of a variety of RNA or proteins in radioresistance, and suggests that the modulation of their expression may constitute a novel radiosensitization approach. Here, we investigated the ability of collectrin (CLTRN) to enhance the radiosensitivity in HCC patients for the rst time. Methods Transcriptome sequencing technology (RNA-seq technology) was used to analyze the transcription-level changes in the genes from the HepG2 cells before and after X-ray irradiation. Combining the results with the HCC tissue RNA-seq data, we determined the ultimate target gene through bioinformatics analysis and cellular veri cation. A series of cellular and molecular biology techniques were applied in vitro and in vivo to con rm whether CLTRN can enhance radiosensitivity in HCC cells. Subsequently, the downstream action mechanism, the upstream transcription factor, and the interaction proteins of CLTRN were determined. Results First, we con rmed the association between CLTRN and radiosensitivity. We observed that CLTRN overexpression led to a signi cant reduction in the proliferation, migration, and invasion potential of Xray-irradiated HCC cells, whereas no observable effect was exerted on cell cycle and apoptosis. The same results were observed in nude mice in vivo. Investigation of the gene regulatory mechanism revealed that the genes analyzed at transcriptome level after CLTRN overexpression were mostly enriched in the glutathione metabolic pathway. As glutathione metabolism forms a vital link in ferroptosis, we surmised that CLTRN is associated with ferroptosis. This was con rmed through the detection of cellular iron, ROS level determination, transmission electron microscopy, and monitoring of ferroptosis-related protein indicators. Lastly, we investigated whether nuclear respiratory factor 1 (NRF1) is the upstream transcription factor of CLTRN, and whether dihydrolipoamide dehydrogenase (DLD) and members of the RAS oncogene family (RAN) are its interacting proteins. Conclusion Our results indicate that CLTRN is a vital regulator of radiation sensitivity and could serve as a novel therapeutic target or prognostic marker in HCC treatment.

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“…Dihydrolipoyl dehydrogenase or dihydrolipoamide dehydrogenase (DLD) is a subunit of pyruvate dehydrogenase complex (PDC) which is known to modulate cellular energy metabolism and homeostasis [56,57]. DLD produces reactive oxygen species (ROS) from its oxidoreductive activity [58][59][60]. Normal cells produce ROS as a way of regulating homeostasis, but tumor cells produce even more, as they can withstand higher levels of ROS.…”

Section: Discussionmentioning

confidence: 99%

“…However, after exceeding the limit that these cells can withstand, they become more susceptible to ROS action, leading tumor cells to apoptosis. Therefore, the use of ROS may be favorable in the treatment of cancer [59,60]. The use of DLDH, in conjunction with chemotherapy drugs, induces to apoptosis of melanoma cells cultured in vitro, but not of normal cells [59].…”

Section: Discussionmentioning

confidence: 99%

Proteomics Approach of Rapamycin Anti-Tumoral Effect on Primary and Metastatic Canine Mammary Tumor Cells In Vitro

et al. 2021

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Rapamycin is an antifungal drug with antitumor activity and acts inhibiting the mTOR complex. Due to drug antitumor potential, the aim of this study was to evaluate its effect on a preclinical model of primary mammary gland tumors and their metastases from female dogs. Four cell lines from our cell bank, two from primary canine mammary tumors (UNESP-CM1, UNESP-CM60) and two metastases (UNESP-MM1, and UNESP-MM4) were cultured in vitro and investigated for rapamycin IC50. Then, cell lines were treated with rapamycin IC50 dose and mRNA and protein were extracted in treated and non-treated cells to perform AKT, mTOR, PTEN and 4EBP1 gene expression and global proteomics by mass spectrometry. MTT assay demonstrated rapamycin IC50 dose for all different tumor cells between 2 and 10 μM. RT-qPCR from cultured cells, control versus treated group and primary tumor cells versus metastatic tumor cells, did not shown statistical differences. In proteomics were found 273 proteins in all groups, and after data normalization 49 and 92 proteins were used for statistical analysis for comparisons between control versus rapamycin treatment groups, and metastasis versus primary tumor versus metastasis rapamycin versus primary tumor rapamycin, respectively. Considering the two statistical analysis, four proteins, phosphoglycerate mutase, malate dehydrogenase, l-lactate dehydrogenase and nucleolin were found in decreased abundance in the rapamycin group and they are related with cellular metabolic processes and enhanced tumor malignant behavior. Two proteins, dihydrolipoamide dehydrogenase and superoxide dismutase, also related with metabolic processes, were found in higher abundance in rapamycin group and are associated with apoptosis. The results suggested that rapamycin was able to inhibit cell growth of mammary gland tumor and metastatic tumors cells in vitro, however, concentrations needed to reach the IC50 were higher when compared to other studies.

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Targeting the Achilles’ heel of cancer cells via integrin-mediated delivery of ROS-generating dihydrolipoamide dehydrogenase

Cited by 32 publications

References 49 publications

<p>Integrin α5/ITGA5 Promotes The Proliferation, Migration, Invasion And Progression Of Oral Squamous Carcinoma By Epithelial–Mesenchymal Transition</p>

<p>Integrin α5/ITGA5 Promotes The Proliferation, Migration, Invasion And Progression Of Oral Squamous Carcinoma By Epithelial–Mesenchymal Transition</p>

CLTRN, Regulated by NRF1/RAN/DLD Protein Complex, Enhances Radiation Sensitivity of Hepatocellular Carcinoma Cells Through Ferroptosis Pathway

Proteomics Approach of Rapamycin Anti-Tumoral Effect on Primary and Metastatic Canine Mammary Tumor Cells In Vitro

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