E1a promotes c-Myc-dependent replicative stress

Valero, María Llanos; Cimas, Francisco J.; Arias, L. Renea; Melgar–Rojas, Pedro; García, Elena; Callejas‐Valera, Juan Luis; García-Cano, Jesús; Serrano-Oviedo, Leticia; Cruz-Morcillo, Miguel A. de la; Sánchez‐Pérez, Isabel; Sánchez‐Prieto, Ricardo

doi:10.4161/cc.26754

Cited by 12 publications

(10 citation statements)

References 53 publications

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“…Previous studies from our laboratory suggested that Chk1 levels could be used as a predictive biomarker of therapeutic response in colon cancer 32 . Furthermore, we demostratred that E1A upregulates Chk1 and this correlates with glioblastoma radiosensitivity 33 . Here, we prove that Chk1 is overexpressed in a disseminated GC cell line, MKN45.…”

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confidence: 78%

CHK1 expression in Gastric Cancer is modulated by p53 and RB1/E2F1: implications in chemo/radiotherapy response

Bargiela-Iparraguirre

Prado-Marchal

Fernández-Fuente

et al. 2016

Sci Rep

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Radiation has a limited but relevant role in the adjuvant therapy of gastric cancer (GC) patients. Since Chk1 plays a critical function in cellular response to genotoxic agents, we aimed to analyze the role of Chk1 in GC as a biomarker for radiotherapy resistance. We analyzed Chk1 expression in AGS and MKN45 human GC cell lines by RT-QPCR and WB and in a small cohort of human patient’s samples. We demonstrated that Chk1 overexpression specifically increases resistance to radiation in GC cells. Accordingly, abrogation of Chk1 activity with UCN-01 and its expression with shChk1 increased sensitivity to bleomycin and radiation. Furthermore, when we assessed Chk1 expression in human samples, we found a correlation between nuclear Chk1 accumulation and a decrease in progression free survival. Moreover, using a luciferase assay we found that Chk1’s expression is controlled by p53 and RB/E2F1 at the transcriptional level. Additionally, we present preliminary data suggesting a posttranscriptional regulation mechanism, involving miR-195 and miR-503, which are inversely correlated with expression of Chk1 in radioresistant cells. In conclusion, Chk1/microRNA axis is involved in resistance to radiation in GC, and suggests Chk1 as a potential tool for optimal stratification of patients susceptible to receive adjuvant radiotherapy after surgery.

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confidence: 78%

CHK1 expression in Gastric Cancer is modulated by p53 and RB1/E2F1: implications in chemo/radiotherapy response

Bargiela-Iparraguirre

Prado-Marchal

Fernández-Fuente

et al. 2016

Sci Rep

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“…E1a isoform 13s was obtained by PCR from cDNA of 293T cells and cloned in PCDNA3.1 and then subcloned into pLESIP vector. This construct has been previously described [ 9 ]. pLESIP-E1a 12s was obtained by PCR cloning from pLPC vector kindly provided by Dr. Scott Lowe's lab (Memorial Sloan-Kettering Cancer Center, New York, New York USA).…”

Section: Methodsmentioning

confidence: 99%

“…Lentiviral production and infection was performed as previously described [ 9 , 64 ]. Briefly, HEK293T cells were transfected overnight using calcium phosphate with 9 μg of pLESIP E1a 13s, pLKO-shRNA for MKP1 or pLKO empty vector plus 6μg of PSPAX2, and 3 μg of the viral envelope protein (VSVG).…”

Section: Methodsmentioning

confidence: 99%

“…However, E1a also has an antitumor effect exerted by different mechanism as reversing the transformed phenotype, inhibiting metastasis, or inducing apoptosis in different experimental models [ 2 – 4 ] (for a review see [ 5 ]). From the therapeutic point of view is well stablished that E1a is able to promote radio/chemosensitivity [ 6 – 9 ]. In this regard, the ability of the adenoviral protein to induce sensitivity could be explained by different mechanisms.…”

Section: Introductionmentioning

confidence: 99%

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MKP1 mediates chemosensitizer effects of E1a in response to cisplatin in non-small cell lung carcinoma cells

et al. 2015

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The adenoviral gene E1a is known to enhance the antitumor effect of cisplatin, one of the cornerstones of the current cancer chemotherapy. Here we study the molecular basis of E1a mediated sensitivity to cisplatin in an experimental model of Non-small cell lung cancer. Our data show how E1a blocks the induction of autophagy triggered by cisplatin and promotes the apoptotic response in resistant cells. Interestingly, at the molecular level, we present evidences showing how the phosphatase MKP1 is a major determinant of cisplatin sensitivity and its upregulation is strictly required for the induction of chemosensitivity mediated by E1a. Indeed, E1a is almost unable to promote sensitivity in H460, in which the high expression of MKP1 remains unaffected by E1a. However, in resistant cell as H1299, H23 or H661, which display low levels of MKP1, E1a expression promotes a dramatic increase in the amount of MKP1 correlating with cisplatin sensitivity. Furthermore, effective knock down of MKP1 in H1299 E1a expressing cells restores resistance to a similar extent than parental cells.In summary, the present work reinforce the critical role of MKP1 in the cellular response to cisplatin highlighting the importance of this phosphatase in future gene therapy approach based on E1a gene.

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“…A lot of researches have shown the apparent links between some genes and/or gene‐induced proteins (such as p53, early region 1A (E1A), survivin, VEGF and ataxia telangiectasia mutated (ATM)) and radiation, because these gene materials can regulate the expression of radiation‐related protein and thus get the goal of tumor radiosensitization. For example, anti‐ATM oligodeoxynucleotides and anti‐survivin siRNA are the common gene materials for radiosensitization.…”

Section: General Strategies Of Nanomaterial‐mediated Tumor Radiosensimentioning

confidence: 99%

Emerging Strategies of Nanomaterial‐Mediated Tumor Radiosensitization

et al. 2018

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Nano-radiosensitization has been a hot concept for the past ten years, and the nanomaterial-mediated tumor radiosensitization method is mainly focused on increasing intracellular radiation deposition by high atomic number (high Z) nanomaterials, particularly gold (Au)-mediated radiation enhancement. Recently, various new nanomaterial-mediated radiosensitive approaches have been successively reported, such as catalyzing reactive oxygen species (ROS) generation, consuming intracellular reduced glutathione (GSH), overcoming tumor hypoxia, and various synergistic radiotherapy ways. These strategies may open a new avenue for enhancing the radiotherapeutic effect and avoiding its side effects. Nevertheless, reviews systematically summarizing these newly emerging methods and their radiosensitive mechanisms are still rare. Therefore, the general strategies of nanomaterial-mediated tumor radiosensitization are comprehensively summarized, particularly aiming at introducing the emerging radiosensitive methods. The strategies are divided into three general parts. First, methods on account of the intrinsic radiosensitive properties of nanoradiosensitizers for radiosensitization are highlighted. Then, newly developed synergistic strategies based on multifunctional nanomaterials for enhancing radiotherapy efficacy are emphasized. Third, nanomaterial-mediated radioprotection approaches for increasing the radiotherapeutic ratio are discussed. Importantly, the clinical translation of nanomaterial-mediated tumor radiosensitization is also covered. Finally, further challenges and outlooks in this field are discussed.

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E1a promotes c-Myc-dependent replicative stress

Cited by 12 publications

References 53 publications

CHK1 expression in Gastric Cancer is modulated by p53 and RB1/E2F1: implications in chemo/radiotherapy response

CHK1 expression in Gastric Cancer is modulated by p53 and RB1/E2F1: implications in chemo/radiotherapy response

MKP1 mediates chemosensitizer effects of E1a in response to cisplatin in non-small cell lung carcinoma cells

Emerging Strategies of Nanomaterial‐Mediated Tumor Radiosensitization

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