CDK2/4 regulate retinoic acid-induced G1 arrest in hepatocellular carcinoma cells

Jung, Hae-Yun; Yoo, Young; Kim, Jun Suk; Kim, Yeul Hong

doi:10.1016/j.hepres.2004.12.006

Cited by 14 publications

(10 citation statements)

References 31 publications

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“…Concomitant with an arrest in G1, ATRA decreases the expression and activity of CDK2 and CDK4 in the two cell lines. On the other hand, Hep3B and SNU449 cells, which are relatively resistant to retinoids, progress into the S/G2+M phase and show increased CDK2 and CDK4 activity [294]. In Hep3B, ATRA has also been reported to exert the opposite effect, down-modulating CDK2 kinase activity and reducing CDK4 expression without affecting the levels of cyclins A, B, D1, D3, or E [295,296].…”

Section: Retinoids and Cyclin Dependent Kinasesmentioning

confidence: 99%

Retinoids as Differentiating Agents in Oncology: A Network of Interactions with Intracellular Pathways as the Basis for Rational Therapeutic Combinations

Garattini¹,

Giannı̀²,

Terao

2007

CPD

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Retinoic acid and natural as well as synthetic derivatives (retinoids) are promising anti-neoplastic agents endowed with both therapeutic and chemopreventive potential. Although the treatment of acute promyelocic leukemia with all-trans retinoic acid is an outstanding example, the full potential of retinoids in oncology has not yet been exploited and a more generalized use of these compounds is not yet a reality. This may be the result of issues such as natural and induced resistance as well as local and systemic toxicity. One way to enhance the therapeutic and chemopreventive activity of retinoic acid and derivatives is to identify rational combinations between these compounds and other pharmacological agents. This is now possible given the wealth of information available on the biochemical and molecular mechanisms underlying the biological activity of retinoids. At the cellular level, the anti-leukemia and anti-cancer activity of retinoids is the result of three main actions, cell-differentiation, growth inhibition and apoptosis. At the molecular level, retinoids act through the activation of nuclear-retinoic-acid-receptor-dependent and-independent pathways. The cellular pathways and molecular networks relevant for retinoid activity are modulated by a panoply of other intra-cellular and extra-cellular pathways that may be targeted by known drugs and other experimental therapeutics. The review article aims to summarize and critically discuss the available knowledge in the field and provide a rational framework that may be useful for the design of effective drug combinations with the potential to enhance the therapeutic index of retinoids.

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Section: Retinoids and Cyclin Dependent Kinasesmentioning

confidence: 99%

Retinoids as Differentiating Agents in Oncology: A Network of Interactions with Intracellular Pathways as the Basis for Rational Therapeutic Combinations

Garattini¹,

Giannı̀²,

Terao

2007

CPD

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“…tion and suppressor of tumor growth by cell cycle arrest and apoptosis. A recent paper [73] showed that the growth inhibitory effect of RA, in HCC, appeared to be CDKs dependent. The inhibition of CDK2 or 4 activities determined sensitization of HCC cells to RA to hypothesize a combined therapy with other cyclin/CDK inhibitors such as UCN01 or flavopiridol as a useful targeted therapy strategy for HCC.…”

Section: Cell Cycle Regulation Pathway and Its Ther-apymentioning

confidence: 99%

Molecular Pathways and Related Target Therapies in Liver Carcinoma

Tommasi

Pinto

Pilato³

et al. 2007

CPD

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Hepatocellular carcinoma (HCC) is a frequent neoplasia which still misses a therapeutical gold standard. Recently, new acquisitions in cancerogenesis process evidenced the genetic and epigenetic alterations of genes involved in the different metabolic pathways of liver cancer suggesting that antibodies, small molecules, demethylating agents, etc. specifically acting against molecular target can be utilized alone or in combination in clinical practice. The main altered targets are: cell membrane receptors, in particular tyrosine kinase receptors, factors involved in cell signalling, specifically Wnt/beta-catenin, Ras/Raf/MEK/ERK and PI3K/Akt/mTOR pathways, proteins linked to cell cycle regulation pathway (i.e. p53, p16/INK4, cyclin/cdk complex) or in invasiveness (EMT, TGFbeta) and proteins involved in DNA metabolism. Genetic or epigenetic changes in these molecules have been used in preclinical settings and, some of them also in clinical trials of phase II and III. This scenario opens new avenues for the prevention and the treatment of HCC. In the present review the main metabolic pathways and molecular alterations have been described together with recent advances in molecular and gene therapy.

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“…In human hepatoma-derived HepG2 cells, ATRA inhibits G1/S transition in the cell cycle and results in growth arrest (13). We investigated the transcriptional regulatory cascades involved in the growth arrest of HepG2 cells induced by ATRA.…”

Section: Introductionmentioning

confidence: 99%

Identification of transcriptional regulatory cascades in retinoic acid-induced growth arrest of HepG2 cells

Nakanishi

Tomaru

Miura

et al. 2008

Nucleic Acids Research

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All-trans retinoic acid (ATRA) is a potent inducer of cell differentiation and growth arrest. Here, we investigated ATRA-induced regulatory cascades associated with growth arrest of the human hepatoma cell line HepG2. ATRA induced >2-fold changes in the expression of 402 genes including 55 linked to cell-cycle regulation, cell growth or apoptosis during 48 h treatment. Computational search predicted that 250 transcriptional regulatory factors (TRFs) could recognize the proximal upstream regions of any of the 55 genes. Expression of 61 TRF genes was significantly changed during ATRA incubation, providing many potential regulatory edges. We focused on six TRFs that could regulate many of the 55 genes and found a total of 160 potential edges in which the expression of each of the genes was changed later than the expression change of the corresponding regulator. RNAi knockdown of the selected TRFs caused perturbation of the respective potential targets. The genes showed an opposite regulation pattern by ATRA and specific siRNA treatments were selected as strong candidates for direct TRF targets. Finally, 36 transcriptional regulatory edges were validated by chromatin immunoprecipitation. These analyses enabled us to depict a part of the transcriptional regulatory cascades closely linked to ATRA-induced cell growth arrest.

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CDK2/4 regulate retinoic acid-induced G1 arrest in hepatocellular carcinoma cells

Cited by 14 publications

References 31 publications

Retinoids as Differentiating Agents in Oncology: A Network of Interactions with Intracellular Pathways as the Basis for Rational Therapeutic Combinations

Retinoids as Differentiating Agents in Oncology: A Network of Interactions with Intracellular Pathways as the Basis for Rational Therapeutic Combinations

Molecular Pathways and Related Target Therapies in Liver Carcinoma

Identification of transcriptional regulatory cascades in retinoic acid-induced growth arrest of HepG2 cells

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