Dependency of Cholangiocarcinoma on Cyclin D–Dependent Kinase Activity

Sittithumcharee, Gunya; Suppramote, Orawan; Vaeteewoottacharn, Kulthida; Sirisuksakun, Chumphon; Jamnongsong, Supawan; Laphanuwat, Phatthamon; Suntiparpluacha, Monthira; Matha, Arriya; Chusorn, Porncheera; Buraphat, Pongsakorn; Kakanaporn, Chumpot; Charngkaew, Komgrid; Silsirivanit, Atit; Korphaisarn, Krittiya; Limsrichamrern, Somchai; Tripatara, Pinpat; Pairojkul, Chawalit; Wongkham, Sopit; Sampattavanich, Somponnat; Okada, Seiji; Jirawatnotai, Siwanon

doi:10.1002/hep.30704

Cited by 24 publications

(32 citation statements)

References 41 publications

(42 reference statements)

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“…CDK4/6 amplification and overexpression is reported in breast and other tumors 39 , 40 . A recent study 41 showed dependency of CCA on cyclin D-dependent kinase activity. The analysis of CCA tumor samples employing TCGA database indicated CDK4 and CDK6 overexpression versus normal samples.…”

Section: Discussionmentioning

confidence: 98%

Dinaciclib, a cyclin-dependent kinase inhibitor, suppresses cholangiocarcinoma growth by targeting CDK2/5/9

Saqub

Proetsch-Gugerbauer

Bezrookove

et al. 2020

Sci Rep

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Cholangiocarcinoma (CCA) is a highly invasive cancer, diagnosed at an advanced stage, and refractory to surgical intervention and chemotherapy. Cyclin-dependent kinases (CDKs) regulate cell cycle progression and transcriptional processes, and are considered potential therapeutic targets for cancer. Dinaciclib is a small molecule multi-CDK inhibitor targeting CDK 2/5/9. In this study, the therapeutic efficacy of dinaciclib was assessed using patient-derived xenograft cells (PDXC) and CCA cell lines. Treatment with dinaciclib significantly suppressed cell proliferation, induced caspase 3/7 levels and apoptotic activity in PDXC and CCA cell lines. Dinaciclib suppressed expression of its molecular targets CDK2/5/9, and anti-apoptotic BCL-XL and BCL2 proteins. Despite the presence of cyclin D1 amplification in the PDXC line, palbociclib treatment had no effect on cell proliferation, cell cycle or apoptosis in the PDXC as well as other CCA cell lines. Importantly, dinaciclib, in combination with gemcitabine, produced a robust and sustained inhibition of tumor progression in vivo in a PDX mouse model, greater than either of the treatments alone. Expression levels of two proliferative markers, phospho-histone H3 and Ki-67, were substantially suppressed in samples treated with the combination regimen. Our results identify dinaciclib as a novel and potent therapeutic agent alone or in combination with gemcitabine for the treatment of CCA.

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Section: Discussionmentioning

confidence: 98%

Dinaciclib, a cyclin-dependent kinase inhibitor, suppresses cholangiocarcinoma growth by targeting CDK2/5/9

Saqub

Proetsch-Gugerbauer

Bezrookove

et al. 2020

Sci Rep

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“…Since nude mice have benefits such as a relatively high engraftment ratios of gastrointestinal tumors, easy observation of subcutaneous tumors, and relatively low price, they remain an important resource for PDX establishment [31,53,62]. The BRJ mice have been used as alternative recipients of cholangiocarcinoma PDX, with a high engraftment ratio (75%) [57,63]. Other solid tumors, such as head and neck tumors, gastric cancers, and bladder cancers, are now under investigation.…”

Section: Establishment Of Pdx Models Using Various Immunocompromismentioning

confidence: 99%

Application of Highly Immunocompromised Mice for the Establishment of Patient-Derived Xenograft (PDX) Models

Okada

Vaeteewoottacharn

Kariya

2019

Cells

185

184

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Patient-derived xenograft (PDX) models are created by engraftment of patient tumor tissues into immunocompetent mice. Since a PDX model retains the characteristics of the primary patient tumor including gene expression profiles and drug responses, it has become the most reliable in vivo human cancer model. The engraftment rate increases with the introduction of Non-obese diabetic Severe combined immunodeficiency (NOD/SCID)-based immunocompromised mice, especially the NK-deficient NOD strains NOD/SCID/interleukin-2 receptor gamma chain(IL2Rγ)null (NOG/NSG) and NOD/SCID/Jak3(Janus kinase 3)null (NOJ). Success rates differ with tumor origin: gastrointestinal tumors acquire a higher engraftment rate, while the rate is lower for breast cancers. Subcutaneous transplantation is the most popular method to establish PDX, but some tumors require specific environments, e.g., orthotropic or renal capsule transplantation. Human hormone treatment is necessary to establish hormone-dependent cancers such as prostate and breast cancers. PDX mice with human hematopoietic and immune systems (humanized PDX) are powerful tools for the analysis of tumor–immune system interaction and evaluation of immunotherapy response. A PDX biobank equipped with patients’ clinical data, gene-expression patterns, mutational statuses, tumor tissue architects, and drug responsiveness will be an authoritative resource for developing specific tumor biomarkers for chemotherapeutic predictions, creating individualized therapy, and establishing precise cancer medicine.

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“…Cyclins are known to regulate cell cycle by modulating the activity of cyclindependent kinases (CDKs). Deregulation of the cell cycle through changes in the activity of cell cycle CDKs or their regulators form essential determinants of human cancers [120][121][122][123][124][125][126][127].…”

Section: Cyclinsmentioning

confidence: 99%

Molecular crosstalk between cancer and neurodegenerative diseases

Seo

Park

2019

Cell. Mol. Life Sci.

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The progression of cancers and neurodegenerative disorders is largely defined by a set of molecular determinants that are either complementarily deregulated, or share remarkably overlapping functional pathways. A large number of such molecules have been demonstrated to be involved in the progression of both diseases. In this review, we particularly discuss our current knowledge on p53, cyclin D, cyclin E, cyclin F, Pin1 and protein phosphatase 2A, and their implications in the shared or distinct pathways that lead to cancers or neurodegenerative diseases. In addition, we focus on the interdependent regulation of brain cancers and neurodegeneration, mediated by intercellular communication between tumor and neuronal cells in the brain through the extracellular microenvironment. Finally, we shed light on the therapeutic perspectives for the treatment of both cancer and neurodegenerative disorders. Keywords Age-related diseases • Cell death • Cell survival • Redox system • Glioma • Neurotoxicity Abbreviations Aβ Amyloid-β AD Alzheimer's disease ALS Amyotrophic lateral sclerosis AMPA α-Amino-3-hydroxy-5-methyl-4isoxazolepropionate APC/C Anaphase promoting complex/ cyclosome APP Amyloid precursor protein ATRA All-trans retinoic acid APL Acute promyelocytic leukemia Bax Bcl-2 associated X BH3 Bcl-2 homology 3 Bim Bcl-2-interacting mediator of cell death BimEL Bim-extra long CDK Cyclin-dependent kinase Cellular and Molecular Life Sciences

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Dependency of Cholangiocarcinoma on Cyclin D–Dependent Kinase Activity

Cited by 24 publications

References 41 publications

Dinaciclib, a cyclin-dependent kinase inhibitor, suppresses cholangiocarcinoma growth by targeting CDK2/5/9

Dinaciclib, a cyclin-dependent kinase inhibitor, suppresses cholangiocarcinoma growth by targeting CDK2/5/9

Application of Highly Immunocompromised Mice for the Establishment of Patient-Derived Xenograft (PDX) Models

Molecular crosstalk between cancer and neurodegenerative diseases

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