p53 and cell cycle independent dysregulation of autophagy in chronic lymphocytic leukaemia

Groves, Michael J.; Johnson, Charlotte E.; James, John; Prescott, Alan R.; Cunningham, Joan; Haydock, Sally; Pepper, Chris; Fegan, Christopher; Pirrie, Lisa; Westwood, Nicholas J.; Coates, Philip J.; Ganley, Ian G.; Tauro, Sudhir

doi:10.1038/bjc.2013.601

Cited by 13 publications

(25 citation statements)

References 39 publications

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“…As this drug inhibits SIRT1 from deacetylating p53 at K382 in several tumor cells stabilizing p53 expression and reactivating its apoptotic function, 4 , 5 , 6 we hypothesized that acetylation of K382- p53 could be as well compromised in Tv6-treated sarcoma cells; however, we found that the antiproliferative effect of Tv6 was independent of the p53 gene status (wild type or mutated), K382- p53 acetylation or apoptotic function. Similar results showing that Tv6 has antitumor activity independent on p53 gene status have been reported for chronic lymphocytic leukemia 21 and gastric cancer models. 22…”

Section: Discussionsupporting

confidence: 86%

SIRT1 and SIRT2 inhibition impairs pediatric soft tissue sarcoma growth

Maruwge

Strambi

et al. 2014

Cell Death Dis

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Sirtuins are NAD+ dependent deacetylases and/or ADP-ribosyl transferases active on histone and non-histone substrates. The first sirtuin was discovered as a transcriptional repressor of the mating-type-loci (Silent Information Regulator sir2) in the budding yeast, where it was shown to extend yeast lifespan. Seven mammalian sirtuins (SIRT1-7) have been now identified with distinct subcellular localization, enzymatic activities and substrates. These enzymes regulate cellular processes such as metabolism, cell survival, differentiation, DNA repair and they are implicated in the pathogenesis of solid tumors and leukemias. The purpose of the present study was to investigate the role of sirtuin expression, activity and inhibition in the survival of pediatric sarcoma cell lines.We have analyzed the expression of SIRT1 and SIRT2 in a series of pediatric sarcoma tumor cell lines and normal cells, and we have evaluated the activity of the sirtuin inhibitor and p53 activator tenovin-6 (Tv6) in synovial sarcoma and rhabdomyosarcoma cell lines. We show that SIRT1 is overexpressed in synovial sarcoma biopsies and cell lines in comparison with normal mesenchymal cells. Tv6 induced apoptosis as well as impaired autophagy flux. Using siRNA to knock down SIRT1 and SIRT2, we show that the expression of both proteins is crucial for the survival of rhabdomyosarcoma cells and that the loss of SIRT1 expression results in a decreased LC3II expression. Our results show that SIRT1 and SIRT2 expressions are crucial for the survival of synovial sarcomas and rhabdomyosarcomas, and demonstrate that the pharmacological inhibition of sirtuins impairs the autophagy process and induces tumor cell death.

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Section: Discussionsupporting

confidence: 86%

SIRT1 and SIRT2 inhibition impairs pediatric soft tissue sarcoma growth

Maruwge

Strambi

et al. 2014

Cell Death Dis

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“…Tenovin-6 has since been used as an inhibitor of sirtuins, especially SIRT1, and has been demonstrated to have a promising anti-neoplastic effect in vitro and in vivo on various hematopoietic malignancies of both lymphoid and myeloid lineages [9–13, 15, 18, 19]. However, whether tenovin-6 is effective against DLBCL has not been investigated so far.…”

Section: Introductionmentioning

confidence: 99%

Tenovin-6 inhibits proliferation and survival of diffuse large B-cell lymphoma cells by blocking autophagy

Yuan

Cheng

et al. 2017

Oncotarget

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Diffuse large B-cell lymphoma (DLBCL) is one of the most aggressive non-Hodgkin lymphomas. It is curable but one-third of cases are refractory to therapy or relapse after initial response highlighting the urgent need for developing novel therapeutic approaches. Targeting sirtuins, particularly SIRT1 by genetic approaches or using pharmaceutical inhibitor tenovin-6, has shown promising therapeutic potential in various hematopoietic malignancies. However, it remains unknown whether these approaches are effective for DLBCL. In this study, we have found that tenovin-6 potently inhibits the proliferation and survival of DLBCL cells. Surprisingly, specific knockdown of SIRT1/2/3 has no effect on DLBCL. Mechanistically, tenovin-6 increases the level of microtubule-associated protein 1 light chain 3B (LC3B)-II in a SIRT1/2/3- and p53-independent manner in DLBCL cell lines. Tenovin-6-mediated increase of LC3B-II is through inhibition of classical autophagy pathway. Furthermore, inhibition of the autophagy pathway by using other inhibitors or by knocking down key genes in the pathway impairs cell proliferation and survival of DLBCL cells. These results indicate that targeting the autophagic pathway could be a novel therapeutic strategy for DLBCL and that precaution should be taken to interpret data where tenovin-6 was used as an inhibitor of sirtuins.

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“…It was reported that p53 is a microtubule-associated protein that monitors the status of micro-tubes directly [63]. Although PTX could not induce genetic damage, it can induce formation of aneuploidy and triggers p53 response, stabilizes microtubules by promoting the distribution of microtubules, then arresting the cell cycle at G0/G1 and G 2 /M period [64]. Studies have shown that selenocysteine inhibits the depolymerization of microtubular proteins during mitosis anaphase and interferes with the mitosis of leukemia cells [47].…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanism for Selective Cytotoxicity towards Cancer Cells of Diselenide-Containing Paclitaxel Nanoparticles

Zhang

et al. 2019

Int. J. Biol. Sci.

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Diselenide-containing paclitaxel nanoparticles (SePTX NPs) indicated selectivity of cytotoxicity between cancerous and normal cells in our previous work. Herein, the mechanism is revealed by molecular biology in detail. Cancer cells and normal cells were treated with the SePTX NPs and cell proliferation was measured using 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) assay and cell morphology. Measurement of reactive oxygen species (ROS) levels and biochemical parameters were employed to monitor oxidative stress of the cells. JC-1 assay was used to detect the mitochondrial dysfunction of the cells. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) analysis was used to detect apoptosis of the cells. Immunofluorescence analysis and western blotting were employed to monitor changes in signaling pathway-related proteins. Compared with PTX, SePTX NPs has a good selectivity to cancer cells and can obviously induce the proliferation damage of cancer cells, but has no significant toxicity to normal cells, indicating that SePTX NPs has a specific killing effect on cancer cells. The results of mechanism research show that SePTX NPs can successfully inhibit the depolymerization of microtubules and induce cell cycle arrest, which is related to the upregulation of p53 and CyclinB1. Simultaneously, SePTX NPs can successfully induce oxidative stress, cause mitochondrial dysfunction, resulting in mitochondrial pathway-mediated apoptosis, which is related to the upregulation of autophagy-related protein LC3-II. On the other hand, lewis lung cancer C57BL/6 mice were used to evaluate the anti-tumor effects of SePTX NPs in vivo. Our data show that SePTX NPs exhibited high inhibiting efficiency against the growth of tumors and were able to reduce the side effects. Collectively, these data indicate that the high antitumor effect and selective cytotoxicities of SePTX NPs is promising in future cancer therapy.

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p53 and cell cycle independent dysregulation of autophagy in chronic lymphocytic leukaemia

Cited by 13 publications

References 39 publications

SIRT1 and SIRT2 inhibition impairs pediatric soft tissue sarcoma growth

SIRT1 and SIRT2 inhibition impairs pediatric soft tissue sarcoma growth

Tenovin-6 inhibits proliferation and survival of diffuse large B-cell lymphoma cells by blocking autophagy

Molecular Mechanism for Selective Cytotoxicity towards Cancer Cells of Diselenide-Containing Paclitaxel Nanoparticles

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