The promise of retinoids to fight against cancer

Altucci, Lucia; Gronemeyer, Hinrich

doi:10.1038/35106036

Cited by 717 publications

(649 citation statements)

References 116 publications

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“…All‐trans retinoic acid, however, can induce retinoic acid syndrome 14 and epidermal hyperplasia, which can lead to excessive scaling 15. Therefore, effective and safe anti‐photoaging agents are still needed.…”

Section: Discussionmentioning

confidence: 99%

Naringenin targets ERK2 and suppresses UVB‐induced photoaging

Jung

et al. 2016

J Cellular Molecular Medi

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A number of natural phytochemicals have anti‐photoaging properties that appear to be mediated through the inhibition of matrix metalloproteinase‐1 (MMP‐1) expression, but their direct target molecule(s) and mechanism(s) remain unclear. We investigated the effect of naringenin, a major flavonoid found in citrus, on UVB‐induced MMP‐1 expression and identified its direct target. The HaCaT human skin keratinocyte cell line and 3‐dimensional (3‐D) human skin equivalent cultures were treated or not treated with naringenin for 1 hr before exposure to UVB. The mechanism and target(s) of naringenin were analysed by kinase assay and multiplex molecular assays. Dorsal skins of hairless mice were exposed to UVB 3 times per week, with a dose of irradiation that was increased weekly by 1 minimal erythema dose (MED; 45 mJ/cm2) to 4 MED over 15 weeks. Wrinkle formation, water loss and water content were then assessed. Naringenin suppressed UVB‐induced MMP‐1 expression and AP‐1 activity, and strongly suppressed UVB‐induced phosphorylation of Fos‐related antigen (FRA)‐1 at Ser265. Importantly, UVB irradiation‐induced FRA1 protein stability was reduced by treatment with naringenin, as well as with a mitogen‐activated protein kinase (MEK) inhibitor. Naringenin significantly suppressed UVB‐induced extracellular signal‐regulated kinase 2 (ERK2) activity and subsequently attenuated UVB‐induced phosphorylation of p90RSK by competitively binding with ATP. Constitutively active MEK (CA‐MEK) increased FRA1 phosphorylation and expression and also induced MMP‐1 expression, whereas dominant‐negative ERK2 (DN‐ERK2) had opposite effects. U0126, a MEK inhibitor, also decreased FRA1 phosphorylation and expression as well as MMP‐1 expression. The photoaging data obtained from mice clearly demonstrated that naringenin significantly inhibited UVB‐induced wrinkle formation, trans‐epidermal water loss and MMP‐13 expression. Naringenin exerts potent anti‐photoaging effects by suppressing ERK2 activity and decreasing FRA1 stability, followed by down‐regulation of AP‐1 transactivation and MMP‐1 expression.

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Section: Discussionmentioning

confidence: 99%

Naringenin targets ERK2 and suppresses UVB‐induced photoaging

Jung

et al. 2016

J Cellular Molecular Medi

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“…Although the consequence of elevated CYP26A1 activity in tumor cells is not clear, clinical observations support the possibility that CYP26A1-mediated catabolism could be involved in abrogating the beneficial tumorsuppressive effects of endogenous RA and the optimal therapeutic efficacy of exogenous RA (Fenaux and Degos, 1997;Kizaki et al, 1997). Conversely, numerous clinical studies have provided support for the use of RA in the treatment of malignancies and premalignant lesions, as well as for chemoprevention (Lotan, 1996;Altucci and Gronemeyer, 2001). Although a relationship between cellular RA status and tumorigenesis is compelling, it remains to be clarified whether RA depletion through metabolic mechanism might promote tumor development.…”

Section: Introductionmentioning

confidence: 99%

Oncogenic and cell survival properties of the retinoic acid metabolizing enzyme, CYP26A1

2009

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Vitamin A deficiency (VAD) is associated with increased susceptibility to carcinogenesis in animal models and elevated risk for a number of human cancers. Here, we found that CYP26A1, the gene encoding a cytochrome P450 enzyme specifically involved in metabolic inactivation of retinoic acid (RA), the most active vitamin A derivative, is highly expressed in 42% (27/65) of primary breast cancers. We also showed that enhanced expression of CYP26A1 suppresses cellular responses to anoikis and consequently promotes anchorage-independent growth. This transformed phenotype was sufficient to markedly increase tumorigenic and metastatic potential. Suppression of CYP26A1 significantly reversed the CYP26A1-mediated oncogenic characteristics, suggesting a direct link between intracellular RA status and tumorigenicity. Our observations provide strong evidence for oncogenic and cell survival properties of CYP26A1 in carcinogenesis, and suggest mechanisms whereby VAD might promote cancer development.

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“…In order to enhance the effectiveness of this drug in the treatment of tumors, a thorough understanding of signaling pathways involved in its use is needed. Dietary-derived ATRA is the main signaling retinoid in vivo and one of the most potent differentiation inducers for human neuroblastoma in vitro, mediating its actions in part through nuclear receptors [3]. Recently, retinoids have been reported to generate reactive oxygen species (ROS), particularly superoxide, in target tissues, an effect which is coupled with differentiation [4].…”

Section: Introductionmentioning

confidence: 99%

All-trans-retinoic acid induces manganese superoxide dismutase in human neuroblastoma through NF-κB

Kiningham

Cardozo

Cook

et al. 2008

Free Radical Biology and Medicine

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Retinoids are signaling molecules that are involved in proliferation, differentiation and apoptosis during development. Retinoids exert their effects, in part, by binding to nuclear receptors, thereby altering gene expression. Clinical use of retinoids in the treatment of neuroblastoma is of interest due to their success in management of acute promyelocytic leukemia. Using the SK-N-SH human neuroblastoma cell line we investigated the effect of the differentiation agent, all-trans-retinoic acid (ATRA) on manganese superoxide dismutase (MnSOD) expression, an enzyme previously shown to enhance differentiation in vitro. Manganese superoxide dismutase mRNA, protein and activity levels increased in a time dependent manner upon treatment with ATRA. Nuclear levels of the NFκB proteins, p50 and p65, increased within 24 h of ATRA administration. This increase paralleled the degradation of the cytoplasmic inhibitor, IκB-β. Furthermore an increase in DNA binding activity to a NFκB element occurred within a 342 base pair enhancer (I2E) of the SOD2 gene with 10 μM ATRA treatment. Reporter analysis showed that ATRA-mediated I2E dependent luciferase expression was attenuated upon mutation of the NFκB element, suggesting a contribution of this transcription factor in retinoid-mediated upregulation of MnSOD. This study identifies SOD2 to be a retinoid responsive gene and demonstrates activation of the NFκB pathway in response to ATRA treatment of SK-N-SH cells. These results suggest signaling events involving NFκB and SOD2 may contribute to the effects of retinoids used in cancer therapy.

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The promise of retinoids to fight against cancer

Cited by 717 publications

References 116 publications

Naringenin targets ERK2 and suppresses UVB‐induced photoaging

Naringenin targets ERK2 and suppresses UVB‐induced photoaging

Oncogenic and cell survival properties of the retinoic acid metabolizing enzyme, CYP26A1

All-trans-retinoic acid induces manganese superoxide dismutase in human neuroblastoma through NF-κB

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