Polo-like kinase 1 (Plk1) is expressed by cutaneous T-cell lymphomas (CTCLs), and its downregulation promotes cell cycle arrest and apoptosis

Nihal, Minakshi; Stutz, Nathalie; Schmit, Travis L.; Ahmad, Nihal; Wood, Gary S.

doi:10.4161/cc.10.8.15353

Cited by 28 publications

(27 citation statements)

References 42 publications

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“…Cells were transfected with MISSION pLKO.1puro (SHC001V) as a shNS-negative control or shSIRT1 (TRCN0000229680/ 81/ 83) or shp53 (TRCN000003753/ 56), as reported earlier. 49,50 The efficacy of each batch of SIRT1 and p53 shRNA clones derived particles was about 70% and tested via immunoblot analysis for knockdown expression prior to further experiments.…”

Section: Flow Cytometrymentioning

confidence: 99%

SIRT1 is upregulated in cutaneous T-cell lymphoma, and its inhibition induces growth arrest and apoptosis

2013

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Silent information regulator type-1 (SIRT1) is the best-studied member of the Sirtuin (Sir2) family of nicotinamide dinucleotide (NAD)-dependent class III histone deacetylases (HDACs), but has not yet been explored in cutaneous T-cell lymphoma (CTCL). We analyzed five CTCL cell lines and lesional tissues using flow cytometry, immunostaining, immunoblotting, cell death, viability, and apoptosis assays, small-molecule inhibitors, and shRNA knockdown. We found strong SIRT1 expression among CTCL lines relative to normal lymphocytes. CTCL cells in lesional tissues also expressed SIRT1 strongly. SIRT1 knockdown resulted in reduced cellular metabolism and proliferation, increased apoptosis, and PARP cleavage products. Tenovin-1, which reversibly inhibits class III HDACs (SIRT1 and SIRT2), reduced SIRT enzymatic activity and SIRT1 expression and led to increased apoptosis. These alterations were accompanied by increased forkhead box O3 (FoxO3) in several cell lines and increased nuclear p53, as well as acetylated p53 in wtp53 MyLa CTCL line. A combination of class I/II and class III HDACIs (vorinostat and tenovin-1) produced significantly greater growth inhibition, cell death via apoptosis, as well as superior p53 promoter upregulation in wtp53 MyLa cells as compared with either agent alone. This occurred in a partially p53-dependent manner, as these effects were blunted by p53 knockdown. Our results indicate that SIRT1 is strongly expressed in CTCL. Its inhibition results in reduced growth and increased apoptosis of CTCL cells. Furthermore, our findings suggest that some CTCL patients, such as those with wtp53, might benefit more from treatment with a combination of different classes of HDACIs than with a single agent.

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Section: Flow Cytometrymentioning

confidence: 99%

SIRT1 is upregulated in cutaneous T-cell lymphoma, and its inhibition induces growth arrest and apoptosis

2013

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“…It was reported that knock-down of AURKB [18] or PLK1 [19,20] induce G2/M or mitotic arrest. We previously reported that ZNF143 transcriptionally regulated AURKB and PLK1 and that knock-down of ZNF143 decreased these gene expressions and induced G2/M arrest [6].…”

Section: Resultsmentioning

confidence: 99%

Forced Expression of ZNF143 Restrains Cancer Cell Growth

Izumi

Yasuniwa

Akiyama

et al. 2011

Cancers

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We previously reported that the transcription factor Zinc Finger Protein 143 (ZNF143) regulates the expression of genes associated with cell cycle and cell division, and that downregulation of ZNF143 induces cell cycle arrest at G2/M. To assess the function of ZNF143 expression in the cell cycle, we established two cells with forced expression of ZNF143 derived from PC3 prostate cancer cell lines. These cell lines overexpress genes associated with cell cycle and cell division, such as polo-like kinase 1 (PLK1), aurora kinase B (AURKB) and some minichromosome maintenance complex components (MCM). However, the doubling time of cells with forced expression of ZNF143 was approximately twice as long as its control counterpart cell line. Analysis following serum starvation and re-seeding showed that PC3 cells were synchronized at G1 in the cell cycle. Also, ZNF143 expression fluctuated, and was at its lowest level in G2/M. However, PC3 cells with forced expression of ZNF143 synchronized at G2/M, and showed lack of cell cycle-dependent fluctuation of nuclear expression of MCM proteins. Furthermore, G2/M population of both cisplatin-resistant PCDP6 cells over-expressing ZNF143 (derived from PC3 cells) and cells with forced expression of ZNF143 was significantly higher than that of each counterpart, and the doubling time of PCDP6 cells is about 2.5 times longer than that of PC3 cells. These data suggested that fluctuations in ZNF143 expression are required both for gene expression associated with cell cycle and for cell division.

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“…Increased expression has been found with progression and metastasis. Plk1 expression is elevated in CTCL, and in particular is found in tumor-stage and in folliculotropic and erythrodermic types of CTCL 65,66. In vitro studies with both small molecule inhibition and shRNA-mediated knockdown of Plk1 resulted in decreased cell growth, decreased cell viability, G2/M arrest, and apoptosis in CTCL cells 66.…”

Section: Immunologic and Molecular Findings In Mycosis Fungoides And mentioning

confidence: 98%

“…Plk1 expression is elevated in CTCL, and in particular is found in tumor-stage and in folliculotropic and erythrodermic types of CTCL 65,66. In vitro studies with both small molecule inhibition and shRNA-mediated knockdown of Plk1 resulted in decreased cell growth, decreased cell viability, G2/M arrest, and apoptosis in CTCL cells 66. In addition, CTCL cell lines with p53 35 and k - ras 36 mutations appear to be sensitive to Plk inhibition and may serve as biomarkers for patient selection.…”

Section: Immunologic and Molecular Findings In Mycosis Fungoides And mentioning

confidence: 99%

Management of cutaneous T cell lymphoma: new and emerging targets and treatment options

Horwitz²,

Moskowitz³

et al. 2012

CMAR

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Cutaneous T cell lymphomas (CTCL) clinically and biologically represent a heterogeneous group of non-Hodgkin lymphomas, with mycosis fungoides and Sézary syndrome being the most common subtypes. Over the last decade, new immunological and molecular pathways have been identified that not only influence CTCL phenotype and growth, but also provide targets for therapies and prognostication. This review will focus on recent advances in the development of therapeutic agents, including bortezomib, the histone deacetylase inhibitors (vorinostat and romidepsin), and pralatrexate in CTCL.

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Polo-like kinase 1 (Plk1) is expressed by cutaneous T-cell lymphomas (CTCLs), and its downregulation promotes cell cycle arrest and apoptosis

Cited by 28 publications

References 42 publications

SIRT1 is upregulated in cutaneous T-cell lymphoma, and its inhibition induces growth arrest and apoptosis

SIRT1 is upregulated in cutaneous T-cell lymphoma, and its inhibition induces growth arrest and apoptosis

Forced Expression of ZNF143 Restrains Cancer Cell Growth

Management of cutaneous T cell lymphoma: new and emerging targets and treatment options

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