Doxorubicin-induced loss of DNA topoisomerase II and DNMT1- dependent suppression of MiR-125b induces chemoresistance in ALK-positive cells

Congras, Annabelle; Caillet, Nina; Torossian, Nouritza; Quelen, Cathy; Daugrois, Camille; Brousset, Pierre; Lamant, Laurence; Hoareau-Aveilla, Coralie

doi:10.18632/oncotarget.24465

Cited by 19 publications

(17 citation statements)

References 45 publications

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“…Our laboratory showed, for the first time, that NPM-ALK + ALCL cell lines and primary tissues express low levels of several miRNAs mediated by the hypermethylation of their gene promoter. 17,21 Both NPM-ALK and STAT3 activities contributed to epigenetic silencing in NPM-ALK + ALCL cell lines and biopsy specimens by up-regulating and recruiting DNMT1 to the promoter of miR-29a, miR-125b and miR-150. 17,19,21 The repressive methylation catalyzed by DNMT1 can be partially reversed by treatment with 5-aza-2’-deoxycytidine (5-aza-dC, decitabine, Dacogen,® SuperGen Inc., Dublin, CA, USA), a DNMT inhibitor.…”

Section: Introductionmentioning

confidence: 99%

“…17,21 Both NPM-ALK and STAT3 activities contributed to epigenetic silencing in NPM-ALK + ALCL cell lines and biopsy specimens by up-regulating and recruiting DNMT1 to the promoter of miR-29a, miR-125b and miR-150. 17,19,21 The repressive methylation catalyzed by DNMT1 can be partially reversed by treatment with 5-aza-2’-deoxycytidine (5-aza-dC, decitabine, Dacogen,® SuperGen Inc., Dublin, CA, USA), a DNMT inhibitor. This DNA-demethylating agent has been shown to restore miR-497 expression, which is suppressed in HT29 colorectal cancer cells.…”

Section: Introductionmentioning

confidence: 99%

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miR-497 suppresses cycle progression through an axis involving CDK6 in ALK-positive cells

et al. 2018

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Anaplastic large-cell lymphoma, a T-cell neoplasm, is primarily a pediatric disease. Seventy-five percent of pediatric anaplastic large-cell lymphoma cases harbor the chromosomal translocation t(2;5)(p23;q35) leading to the ectopic expression of NPM-ALK, a chimeric tyrosine kinase. NPM-ALK consists of an N-terminal nucleophosmin (NPM) domain fused to an anaplastic lymphoma kinase (ALK) cytoplasmic domain. Pediatric NPM-ALK+ anaplastic large-cell lymphoma is often a disseminated disease and young patients are prone to chemoresistance or relapse shortly after chemotherapeutic treatment. Furthermore, there is no gold standard protocol for the treatment of relapses. To the best of our knowledge, this is the first study on the potential role of the microRNA, miR-497, in NPM-ALK+ anaplastic large-cell lymphoma tumorigenesis. Our results show that miR-497 expression is repressed in NPM-ALK+ cell lines and patient samples through the hypermethylation of its promoter and the activity of NPM-ALK is responsible for this epigenetic repression. We demonstrate that overexpression of miR-497 in human NPM-ALK+ anaplastic large-cell lymphoma cells inhibits cellular growth and causes cell cycle arrest by targeting CDK6, E2F3 and CCNE1, the three regulators of the G1 phase of the cell cycle. Interestingly, we show that a scoring system based on CDK6, E2F3 and CCNE1 expression could help to identify relapsing pediatric patients. In addition, we demonstrate the sensitivity of NPM-ALK+ cells to CDK4/6 inhibition using for the first time a selective inhibitor, palbociclib. Together, our findings suggest that CDK6 could be a therapeutic target for the development of future treatments for NPM-ALK+ anaplastic large-cell lymphoma.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

miR-497 suppresses cycle progression through an axis involving CDK6 in ALK-positive cells

et al. 2018

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“…The translocation and activity of NPM-ALK are responsible for miR-150 and miR-125b silencing in cell lines, mediated by DNMT1-dependent activity [ 181 , 182 ]. Inhibition of DNMT1 binding to the MIR125B1 promoter decreased BAK1 expression, an miR-125b target.…”

Section: Lymphomasmentioning

confidence: 99%

“…Inhibition of DNMT1 binding to the MIR125B1 promoter decreased BAK1 expression, an miR-125b target. Mir-125b repression and increase of BAK1 is correlated with early relapse in human ALK + ALCL biopsies [ 182 ]. Conversely, miR-101 is found downregulated in both types of ALCL, but, because it targets the mammalian/mechanistic target of the rapamycin (mTOR) pathway, its forced expression only affects ALK + cell growth [ 176 ].…”

Section: Lymphomasmentioning

confidence: 99%

MiRNA Dysregulation in Childhood Hematological Cancer

Oliveira

Roberto

Baroni

et al. 2018

IJMS

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For decades, cancer biology focused largely on the protein-encoding genes that have clear roles in tumor development or progression: cell-cycle control, apoptotic evasion, genome instability, drug resistance, or signaling pathways that stimulate growth, angiogenesis, or metastasis. MicroRNAs (miRNAs), however, represent one of the more abundant classes of cell modulators in multicellular organisms and largely contribute to regulating gene expression. Many of the ~2500 miRNAs discovered to date in humans regulate vital biological processes, and their aberrant expression results in pathological and malignant outcomes. In this review, we highlight what has been learned about the roles of miRNAs in some of the most common human pediatric leukemias and lymphomas, along with their value as diagnostic/prognostic factors.

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“…Many reports have proved that of Dox is able to cross the nuclear membrane, intercalate into human DNA, and consequently disrupt DNA repair mediated by Topoisomerase 2. [49][50][51] In fact, accumulation of Dox in the nuclei of HT-1080 cells was seen as a result of treatment with the formulation of MM pre-treated with MMP2 enzymes. The confocal image suggests that the prodrug can indeed release free Dox after going through enzymatic cleavage (Figure 10c).…”

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confidence: 99%

Multi-targeted stimuli-sensitive mixed micelles as a strategy for cancer therapy

Costa¹

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Conventional drugs have for long been investigated as potential therapeutic agents for the treatment of cancer, one of the leading causes of death worldwide. Recently, combination of these drugs with small non-coding RNAs has become a promising strategy to overcome the development of drug resistance. Additionally, the use of stimuli-sensitive drug delivery systems has emerged as a strategy to improve targeting of diseased tissues and reduce the damage to non-targeted organs.The general aim of this study was to develop, characterize and test a pharmaceutical preparation whose action is triggered by the enzymatic activity and redox conditions typical of tumor microenvironments. We hypothesized that overexpression of matrix metalloproteinase 2 (MMP2) and glutathione (GSH) in the tumor would guarantee a targeted delivery of Doxorubicin (Dox) and miRNA-34a, increasing bioavailability of both therapeutic agents and reducing off-target effects.A Dox prodrug and lipid-modified miRNA-34a were successfully synthesized and incorporated into mixed micelles (MM). The stimuli-sensitivity of both components was demonstrated in monolayer and spheroid models of cell culture in vitro. The level of MMP2 expression was a key factor to determine the localization of the Dox prodrug in the cytoplasm or cell nuclei. The cytotoxic effect in a monolayer model of soft tissue sarcoma was as high as 80%. The prodrug was also effective against breast adenocarcinoma and glioblastoma. The treatment with MMP2-sensitive MM significantly reduced cell motility and migration when compared to group control.iii GSH-sensitive MM lowered mRNA levels of survivin (» 55%), Bcl2 (» 65%) and notch1 (» 45%) in soft tissue sarcoma cells. Combination therapy with Dox prodrug and miRNA-34a inhibited over 90% of Bcl2 production. Dual stimuli-sensitive MM killed 2.4 to 3.6 times more cells compared to the single treatments by arresting the cells in S phase of their cell cycle.In vivo trials in tumor-bearing mice significantly inhibited growth of soft tissue sarcoma and glioblastoma xenografts and avoided weight loss caused by free Dox.

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Doxorubicin-induced loss of DNA topoisomerase II and DNMT1- dependent suppression of MiR-125b induces chemoresistance in ALK-positive cells

Cited by 19 publications

References 45 publications

miR-497 suppresses cycle progression through an axis involving CDK6 in ALK-positive cells

miR-497 suppresses cycle progression through an axis involving CDK6 in ALK-positive cells

MiRNA Dysregulation in Childhood Hematological Cancer

Multi-targeted stimuli-sensitive mixed micelles as a strategy for cancer therapy

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