p53 Inhibits Adriamycin-Induced Down-Regulation of Cyclin D1 Expression in Human Cancer Cells

Shao, Jianghua; Teraishi, Fuminori; Katsuda, Koh; Tanaka, Noriaki; Fujiwara, Toshiyoshi

doi:10.1006/bbrc.2001.6314

Cited by 9 publications

(5 citation statements)

References 18 publications

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“…In agreement with these data, sensitivity to H 2 O 2 -induced cell death is increased in PLC-␥1 null cells, where cyclin D1 degradation in response to oxidants is likely disabled (6). Furthermore, cyclin D1 overexpression sensitizes cancer cells to fenretinide and adriamycin, two drugs inducing intracellular oxidative stress (46,47). As expected, when cells were exposed to a lethal dose of H 2 O 2 , cell viability was not altered by the down modulation of cyclin D1 by RNAi (P. Fasanaro and F. Martelli, unpublished observations).…”

Section: Discussionmentioning

confidence: 52%

Cyclin D1 degradation enhances endothelial cell survival upon oxidative stress

et al. 2006

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The understanding of endothelial cell responses to oxidative stress may provide insights into aging mechanisms and into the pathogenesis of numerous cardiovascular diseases. In this study, we examined the regulation and the functional role of cyclin D1, a crucial player in cell proliferation and survival. On H2O2 treatment, endothelial cells showed a rapid down-modulation of cyclin D1. Other D-cyclins were similarly regulated, and this decrease was also observed after exposure to other oxidative stress-inducing stimuli, namely 1,3-bis (2 chloroethyl)-1 nitrosourea treatment and ischemia. H2O2 treatment induced cyclin D1 ubiquitination followed by proteasome degradation. Phospholipase C inhibition prevented cyclin D1 degradation, and its activation triggered cyclin D1 down-modulation in the absence of oxidative stress. Activated phospholipase C generates inositol-1,4,5-trisphosphate (IP3) and Ca2+ release from internal stores. We found that both IP3-receptor inhibition and intracellular Ca2+ chelation prevented cyclin D1 degradation induced by oxidative stress. Furthermore, Ca2+ increase was transduced by Ca2+/calmodulin-dependent protein kinase (CaMK). In fact, H2O2 stimulated CaMK activity, CaMK inhibitors prevented H2O2-induced cyclin D1 down-modulation, and CaMK overexpression induced cyclin D1 degradation. Finally, overriding of cyclin D1 down-modulation via its forced overexpression or via CaMK inhibition increased cell sensitivity to H2O2-induced apoptotic cell death. Thus, cyclin D1 degradation enhances endothelial cell survival on oxidative stress.

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Section: Discussionmentioning

confidence: 52%

Cyclin D1 degradation enhances endothelial cell survival upon oxidative stress

et al. 2006

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“…Lastly, prior work has shown that cyclin D overexpressing cancer cells were more sensitive to doxorubicin. 46 Consequently, irrespective of Smad3 expression status, overexpression of cyclin D1 in the MCF7/CD1 cells should result in increased cell division, and thus greater sensitivity to the cytotoxic effects of doxorubicin chemotherapy, found in Figure 2C.…”

Section: Discussionmentioning

confidence: 93%

CDK4 inhibition and doxorubicin mediate breast cancer cell apoptosis through Smad3 and survivin

Tarasewicz¹,

Hamdan²,

Straehla³

et al. 2014

Cancer Biology & Therapy

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Cyclin D1/CDK4 activity is upregulated in up to 50% of breast cancers and CDK4-mediated phosphorylation negatively regulates the TGFβ superfamily member Smad3. We sought to determine if CDK4 inhibition and doxorubicin chemotherapy could impact Smad3-mediated cell/colony growth and apoptosis in breast cancer cells. Parental and cyclin D1-overexpressing MCF7 cells were treated with CDK4 inhibitor, doxorubicin, or combination therapy and cell proliferation, apoptosis, colony formation, and expression of apoptotic proteins were evaluated using an MTS assay, TUNEL staining, 3D Matrigel assay, and apoptosis array/immunoblotting. Study cells were also transduced with WT Smad3 or a Smad3 construct resistant to CDK4 phosphorylation (5M) and colony formation and expression of apoptotic proteins were assessed. Treatment with CDK4 inhibitor/doxorubicin combination therapy, or transduction with 5M Smad3, resulted in a similar decrease in colony formation. Treating cyclin D overexpressing breast cancer cells with combination therapy also resulted in the greatest increase in apoptosis, resulted in decreased expression of anti-apoptotic proteins survivin and XIAP, and impacted subcellular localization of pro-apoptotic Smac/DIABLO. Additionally, transduction of 5M Smad3 and doxorubicin treatment resulted in the greatest change in apoptotic protein expression. Collectively, this work showed the impact of CDK4 inhibitor-mediated, Smad3-regulated tumor suppression, which was augmented in doxorubicin-treated cyclin D-overexpressing study cells.

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“…Adriamycin downregulates the expression of the cyclin D1, the major regulator of cell cycle into the proliferative stage in several tumor cell lines. 32 It was also reported that doxorubicin suppressed the expression of oncogene c-myc and c-jun in rat glioblastoma cell line. 33 Furthermore, doxorubicin directly inhibits the release of cytokine (eg, IL-6, IFN-␥) from stimulated peripheral mononuclear cell at its nontoxic concentration in vitro.…”

Section: Mechanisms For the Inhibitory Effect Of Nk911 On Neointimal mentioning

confidence: 95%

Application of Nanoparticle Technology for the Prevention of Restenosis After Balloon Injury in Rats

Uwatoku

Shimokawa

Abe

et al. 2003

Circulation Research

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Abstract-Restenosis after percutaneous coronary intervention continues to be a serious problem in clinical cardiology.Recent advances in nanoparticle technology have enabled us to deliver an antiproliferative drug selectively to the balloon-injured artery for a longer time. NK911, which is a core-shell nanoparticle of polyethyleneglycol-based block copolymer encapsulating doxorubicin, accumulates in vascular lesions with increased permeability. We first confirmed that balloon injury caused a marked and sustained increase in vascular permeability (as evaluated by Evans blue staining) for a week in the rat carotid artery. We then observed that intravenous administration of just 3 times of NK911, but not doxorubicin alone, significantly inhibited the neointimal formation of the rat carotid artery at 4 weeks after the injury in both a single-and double-injury model. Immunostaining demonstrated that the effect of NK911 was due to inhibition of vascular smooth muscle proliferation but not to enhancement of apoptosis or inhibition of inflammatory cell recruitment. Measurement of vascular concentrations of doxorubicin confirmed the effective delivery of the agent to the balloon-injured artery by NK911 in both a single-and double-injury model. RNA protection assay demonstrated that NK911 inhibited expression of several cytokines but not that of apoptosis-related molecules. NK911 was well tolerated without any adverse systemic effects. These results suggest that nanoparticle technology to target vascular lesions with increased permeability is a promising and safe approach for the prevention of restenosis after balloon injury.

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p53 Inhibits Adriamycin-Induced Down-Regulation of Cyclin D1 Expression in Human Cancer Cells

Cited by 9 publications

References 18 publications

Cyclin D1 degradation enhances endothelial cell survival upon oxidative stress

Cyclin D1 degradation enhances endothelial cell survival upon oxidative stress

CDK4 inhibition and doxorubicin mediate breast cancer cell apoptosis through Smad3 and survivin

Application of Nanoparticle Technology for the Prevention of Restenosis After Balloon Injury in Rats

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