p21Cip1 Confers resistance to imatinib in human chronic myeloid leukemia cells

Ferrándiz, Nuria; Caraballo, Juan M.; Albajar, Marta; Gómez‐Casares, María Teresa; López-Jorge, C E; Blanco, Rosa; Delgado, M. Dolores; León, Javier

doi:10.1016/j.canlet.2009.11.017

Cited by 18 publications

(14 citation statements)

References 36 publications

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“…GVS and other HDAC inhibitors have been shown to block cells in G1, at least in part through p21CDKN1A induction. Furthermore, p21CDKN1A has been observed to protect cells from apoptosis in most cellular contexts investigated, including chronic myeloid leukemia cells and myelomonocytic cells following HDAC inhibitor treatment [25][26][27][28], reviewed by Gartel and Tyner [29]. Thus, a lack of p21CDKN1A induction in the presence of HU may at least in part explain the increased apoptosis observed in the presence of both compounds.…”

Section: Discussionmentioning

confidence: 96%

Givinostat and hydroxyurea synergize in vitro to induce apoptosis of cells from JAK2V617F myeloproliferative neoplasm patients

Calzada

Pedrini

Finazzi

et al. 2013

Experimental Hematology

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Section: Discussionmentioning

confidence: 96%

Givinostat and hydroxyurea synergize in vitro to induce apoptosis of cells from JAK2V617F myeloproliferative neoplasm patients

Calzada

Pedrini

Finazzi

et al. 2013

Experimental Hematology

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“…In addition, autophagy regulates the ROS-mediated induction of the cell cycle inhibitor CDKN1A/p21 [28], which controls cellular proliferation, contributes to therapy resistance in cancer [29, 30] and controls phosphorylation of extracellular signal-regulated kinase MAPK1/ERK [31], which is a core regulator of p21 [32, 33]. …”

Section: Introductionmentioning

confidence: 99%

C10ORF10/DEPP-mediated ROS accumulation is a critical modulator of FOXO3-induced autophagy

et al. 2017

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BackgroundNeuroblastoma is the most common solid tumor in childhood and develops from undifferentiated progenitor cells of the sympathetic nervous system. In neuronal tumor cells DNA-damaging chemotherapeutic agents activate the transcription factor FOXO3 which regulates the formation of reactive oxygen species (ROS) and cell death as well as a longevity program associated with therapy resistance.We demonstrated before that C10ORF10/DEPP, a transcriptional target of FOXO3, localizes to peroxisomes and mitochondria and impairs cellular ROS detoxification. In the present study, we investigated the impact of FOXO3 and DEPP on the regulation of autophagy. Autophagy serves to reduce oxidative damage as it triggers a self-degradative process for the removal of aggregated or misfolded proteins and damaged organelles.MethodsThe effect of FOXO3 and DEPP on autophagy induction was analyzed using live cell fluorescence microscopy and immunoblot analyses of SH-EP cells transfected with a plasmid for EYFP-LC3 and with siRNAs specific for LC3, respectively. ROS steady-state levels were measured with reduced MitoTrackerRed CM-H2XROS. Cellular apoptosis was analyzed by flow cytometry and the caspase 3/7 assay.ResultsWe report for the first time that DEPP induces ROS accumulation and thereby mediates the formation of autophagosomes as inhibition of ROS formation by N-acetyl-cysteine completely blocks autophagy. We further demonstrate that H2O2-treatment triggers autophagy-induction by FOXO3-mediated DEPP expression. Importantly, knockdown of DEPP was sufficient to efficiently inhibit autophagy-induction under different stress conditions such as serum starvation and genotoxic stress, suggesting that DEPP expression is critical for the initiation of autophagy in neuroblastoma. FOXO3-triggered autophagy partially protects neuroblastoma cells from cell death. Consistent with this concept, we demonstrate that inhibition of autophagy by LC3-knockdown significantly increased etoposide- and doxorubicin-induced apoptosis. These results were also confirmed by the use of the autophagy-inhibitor chloroquine that significantly enhanced the chemotherapeutic effect of etoposide and doxorubicin in neuronal tumor cells.ConclusionTargeting FOXO3/DEPP-triggered autophagy is a promising strategy to sensitize neuroblastoma cells to chemotherapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0661-4) contains supplementary material, which is available to authorized users.

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“…Under the posttranscriptional mechanism, stress-activated protein kinase p38 and JNK1 are involved in p21 stabilization [27]. On the other hand, p21 protects apoptosis in CML cells treated with imatinib [28]. As shown in previous studies, p21 has multiple functions according to stimulus; therefore, we need to clarify how JNK and p53-independent inducible p21 contribute to apoptosis progression to understand AI analog-inducible apoptosis mechanisms.…”

Section: Discussionmentioning

confidence: 95%

“…CML is characterized by the active bcr-abl kinase encoded by a fusion gene produced by a t(9;22) translocation [28]. Although imatinib is the main drug applied in CML treatment, and initial clinical results of imatinib in CML have been encouraging in terms of cytogenetic remission, patients in more advanced disease stages are either initially refractory to imatinib treatment or lose imatinib sensitivity over time and experience relapse [29][30][31].…”

Section: Discussionmentioning

confidence: 99%

Caspase-independent apoptosis induction of quorum-sensing autoinducer analogs against chronic myeloid leukemia K562

et al. 2011

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Quorum sensing is defined as the ability of microorganisms to sense their population density via the release of signaling molecules called autoinducers (AIs). Various types of AI analogs were prepared and their antitumor properties against chronic myeloid leukemia (CML) K562 cells were investigated. Two AI analogs induced progressive apoptosis with JNK activation and p21 induction. In addition, this induction of apoptosis is not related to bcr-abl kinase, which sustains CML proliferation. However, the progression of apoptosis was not inhibited by a caspase family inhibitor. These results suggested that AI analogs could induce caspase-independent apoptosis in CML K562.

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p21Cip1 Confers resistance to imatinib in human chronic myeloid leukemia cells

Cited by 18 publications

References 36 publications

Givinostat and hydroxyurea synergize in vitro to induce apoptosis of cells from JAK2V617F myeloproliferative neoplasm patients

Givinostat and hydroxyurea synergize in vitro to induce apoptosis of cells from JAK2V617F myeloproliferative neoplasm patients

C10ORF10/DEPP-mediated ROS accumulation is a critical modulator of FOXO3-induced autophagy

Caspase-independent apoptosis induction of quorum-sensing autoinducer analogs against chronic myeloid leukemia K562

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