Effect of Retinoic Acid on Apoptosis and DNA Repair in Human Keratinocytes after UVB Irradiation

2000 ◽  
Vol 4 (1) ◽  
pp. 2-7 ◽  
Author(s):  
Gang Li ◽  
Jason A. Bush ◽  
Vincent C. Ho
Keyword(s):  
Dna Repair ◽  
Retinoic Acid ◽  
Skin Cancer ◽  
Human Keratinocytes ◽  
Epidemiological Studies ◽  
Skin Carcinogenesis ◽  
Apoptosis Assay ◽  
Initiation Stage ◽  
Induced Apoptosis ◽  
Damaged Dna

Background: Skin cancer is extremely common. Epidemiological studies indicated that ultraviolet radiation (UV) is the primary cause for skin cancers, and that retinoic acid (RA) is able to inhibit this UV-induced skin carcinogenesis; however, the molecular mechanism of the anti-UV action of RA is unclear. Objective: The purpose of this study is to investigate if RA enhances the removal of UV-induced DNA damage. Methods: The effect of RA on UV-induced apoptosis and DNA repair was investigated by ELISA apoptosis assay and CAT assay. Results: Both all-trans-RA and 9-cis-RA did not promote UV-induced apoptosis nor the repair of UV-damaged DNA in human keratinocytes. Furthermore, RA did not induce the expression of p53. Conclusion: The inhibition of RA on skin carcinogenesis is not due to enhanced removal of UV-damaged DNA. Therefore, RA does not inhibit skin cancer development at the initiation stage, but possibly at the promotion and progression stages.

scholarly journals Specific betapapillomaviruses associated with squamous cell carcinoma of the skin inhibit UVB-induced apoptosis of primary human keratinocytes

2008 ◽  
Vol 89 (9) ◽  
pp. 2303-2314 ◽  
Author(s):  
Linda Struijk ◽  
Els van der Meijden ◽  
Siamaque Kazem ◽  
Jan ter Schegget ◽  
Frank R. de Gruijl ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Human Keratinocytes ◽  
Epidemiological Studies ◽  
Primary Human Keratinocytes ◽  
Carcinogenic Effect ◽  
Uvb Irradiation ◽  
Induced Apoptosis

Epidemiological studies have shown an association between infections by specific betapapillomaviruses, such as human papillomavirus (HPV) types 5 and 8, and cutaneous squamous cell carcinoma (SCC). The role of betapapillomaviruses in the development of cutaneous SCC is, however, still enigmatic. The ability to inhibit UVB-induced apoptosis, as demonstrated for HPV5 in vitro, may be important in this respect, as survival of DNA-damaged and mutated cells increases the risk of transformation. The aim of this study was to assess whether inhibition of UVB-induced apoptosis is a general property of betapapillomaviruses and to identify apoptotic factors that are potentially involved in this process. Primary human keratinocytes transduced with E6 and E7 of selected betapapillomaviruses (HPV5, HPV8, HPV15, HPV20, HPV24 and HPV38) were characterized and subjected to UVB irradiation. HPV8- and HPV20-expressing keratinocytes in particular showed fewer signs of apoptosis, as demonstrated by lower levels of active caspase 3, less enzymic caspase activity and less DNA fragmentation. The observed inhibition of UVB-induced apoptosis was mediated by E6 and coincided with reduced steady-state expression of the pro-apoptotic protein Bax. In conclusion, E6 of HPV8 and HPV20 reduces the apoptotic responses upon UVB irradiation when expressed in primary human keratinocytes. Infections with HPV8 and HPV20 may therefore augment the carcinogenic effect of UV radiation and potentially contribute to oncogenic transformation of the skin.

scholarly journals Identification of master regulator genes of UV response and their implications for skin carcinogenesis

2018 ◽  
Vol 40 (5) ◽  
pp. 687-694 ◽  
Author(s):  
Yao Shen ◽  
Gabriel Chan ◽  
Michael Xie ◽  
Wangyong Zeng ◽  
Liang Liu
Keyword(s):  
Skin Cancer ◽  
Uv Radiation ◽  
Genome Stability ◽  
Thyroid Hormone Receptor ◽  
Human Keratinocytes ◽  
Selective Inhibition ◽  
Skin Carcinogenesis ◽  
Specific Gene ◽  
Protein Activity ◽  
Skin Cell

AbstractSolar UV radiation is a major environmental risk factor for skin cancer. Despite decades of robust and meritorious investigation, our understanding of the mechanisms underlying UV-induced skin carcinogenesis remain incomplete. We previously performed comprehensive transcriptomic profiling in human keratinocytes following exposure to different UV radiation conditions to generate UV-specific gene expression signatures. In this study, we utilized Virtual Inference of Protein Activity by Enriched Regulon (VIPER), a robust systems biology tool, on UV-specific skin cell gene signatures to identify master regulators (MRs) of UV-induced transcriptomic changes. We identified multiple prominent candidate UV MRs, including forkhead box M1 (FOXM1), thyroid hormone receptor interactor 13 and DNA isomerase II alpha, which play important roles in cell cycle regulation and genome stability. MR protein activity was either activated or suppressed by UV in normal keratinocytes. Intriguingly, many of the UV-suppressed MRs were activated in human skin squamous cell carcinomas (SCCs), highlighting their importance in skin cancer development. We further demonstrated that selective inhibition of FOXM1, whose activity was elevated in SCC cells, was detrimental to SCC cell survival. Taken together, our study uncovered novel UV MRs that can be explored as new therapeutic targets for future skin cancer treatment.

scholarly journals Induction, not associated with host-cell re-activation of damaged plasmid DNA, of damaged-DNA-recognition proteins by retinoic acid and dibutyryl cyclic AMP in mammalian cells

1996 ◽  
Vol 313 (2) ◽  
pp. 441-445 ◽  
Author(s):  
Nian-Kang SUN ◽  
Shang-Lang HUANG ◽  
Sue LIN-CHAO ◽  
Chuck C.-K. CHAO
Keyword(s):  
Dna Repair ◽  
Retinoic Acid ◽  
Cyclic Amp ◽  
Mammalian Cells ◽  
Cell Types ◽  
Dibutyryl Cyclic Amp ◽  
Nih3t3 Cells ◽  
Activation Assay ◽  
Cellular Dna ◽  
Damaged Dna

Our previous studies [Chao (1992) Biochem. J. 282, 203-207; C. C.-K. Chao, unpublished work] has suggested a correlation between the levels of constitutive UV-damaged-DNA-recognitionproteins (UVDRP) and cellular DNA repair in different cell types. In the present study, UVDRP were induced in F9 and NIH3T3 cells by 0.1 μM retinoic acid (RA) and 1 mM dibutyryl cyclic AMP (dbcAMP), which is sufficient to induce differentiation in murine F9 stem cells. The induction of UVDRP in F9 and NIH3T3 cells was optimized after 6 and 2 days incubation with RA/dbcAMP respectively. Since NIH3T3 cells were not induced to differentiate by RA/dbcAMP, the up-regulation of the UVDRP in mammalian cells would thus seem not to be mediated directly by differentiation. Using a plasmid re-activation assay to estimate DNA repair, we did not find a correlation between DNA repair and UVDRP in RA/dbcAMP-treated cells. The results suggest that UVDRP may have a function other than, or in addition to, its role in DNA repair.

Interexperimental and Interindividual Variations of DNA Repair Capacities After UV-B and UV-C Irradiations of Human Keratinocytes and Fibroblasts

2004 ◽  
Vol 79 (3) ◽  
pp. 286 ◽  
Author(s):  
Marjorie Chazal ◽  
Emeric Roux ◽  
Claire Alapetite ◽  
Christophe Roulin ◽  
Ethel Moustacchi ◽  
...  
Keyword(s):  
Dna Repair ◽  
Human Keratinocytes ◽  
Interindividual Variations ◽  
Uv C

scholarly journals UVB protective effects of Sargassum horneri through the regulation of Nrf2 mediated antioxidant mechanism

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Eui Jeong Han ◽  
Seo-Young Kim ◽  
Hee-Jin Han ◽  
Hyun-Soo Kim ◽  
Kil-Nam Kim ◽  
...  
Keyword(s):  
Skin Barrier ◽  
Human Keratinocytes ◽  
Underlying Mechanism ◽  
Ultraviolet B ◽  
Sargassum Horneri ◽  
Cellular Damage ◽  
Protective Effects ◽  
Skin Damage ◽  
Antioxidant Mechanism ◽  
Induced Apoptosis

AbstractThe present study aimed to evaluate the protective effect of a methanol extract of Sargassum horneri (SHM), which contains 6-hydroxy-4,4,7a-trimethyl-5,6,7,7a-tetrahydrobenzofuran-2(4H)-one (HTT) and apo-9′-fucoxanthinone, against ultraviolet B (UVB)-induced cellular damage in human keratinocytes and its underlying mechanism. SHM significantly improved cell viability of UVB-exposed human keratinocytes by reducing the generation of intracellular reactive oxygen species (ROS). Moreover, SHM inhibited UVB exposure-induced apoptosis by reducing the formation of apoptotic bodies and the populations of the sub-G1 hypodiploid cells and the early apoptotic cells by modulating the expression of the anti- and pro-apoptotic molecules, Bcl-2 and Bax, respectively. Furthermore, SHM inhibited NF-κB p65 activation by inducing the activation of Nrf2/HO-1 signaling. The cytoprotective and antiapoptotic activities of SHM are abolished by the inhibition of HO-1 signaling. In further study, SHM restored the skin dryness and skin barrier disruption in UVB-exposed human keratinocytes. Based to these results, our study suggests that SHM protects the cells against UVB-induced cellular damages through the Nrf2/HO-1/NF-κB p65 signaling pathway and may be potentially useful for the prevention of UVB-induced skin damage.

scholarly journals Intracellular alpha-fetoprotein interferes with all-trans retinoic acid induced ATG7 expression and autophagy in hepatocellular carcinoma cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shanshan Wang ◽  
Rilu Feng ◽  
Ying Shi ◽  
Dexi Chen ◽  
Honglei Weng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Retinoic Acid ◽  
Carcinoma Cells ◽  
Alpha Fetoprotein ◽  
Cell Counting ◽  
All Trans Retinoic Acid ◽  
Induced Apoptosis ◽  
Anti Tumor Activity ◽  
Retinoid Acid ◽  
Hcc Cells

AbstractRetinoic acid and retinoid acid receptor (RA-RAR) signaling exhibits suppressive functions in the progression of hepatocellular carcinoma (HCC) through multiple mechanisms. However, whether RA-RAR signaling induces autophagy that contributes its anti-tumor activity in HCC remains elusive. In the current study, the effects of RA-RAR pathway on autophagy were investigated in two HCC cell lines: alpha-fetoprotein (AFP) positive PLC/PRF/5 and AFP negative HLE cells. Cell autophagy was analyzed with western blot for detection of LC3 conversion and p62/SQSTM1 degradation while autophagy flux was assayed using the mRFP-GFP-LC3 reporter. Cell apoptosis and viability were analyzed by caspase-3 activity, TdT-mediated dUTP nick end labeling (TUNEL) assay, and Cell Counting Kit (CCK)-8, respectively. Chromatin immunoprecipitation (ChIP) was employed to detect the binding of RAR onto the promoter of autophagy-relevant 7 (ATG7), and co-immunoprecipitation (CoIP) was used to analyze the interaction of AFP and RAR. The results showed that ATRA dosage and time-dependently induced high levels of cell autophagy in both the PLC/PRF/5 and HLE cells, which was accompanied with up-regulation of ATG7. ChIP assay showed that RAR was able to bind to its responsive elements on ATG7 promoter. Impairment of ATG7 induction or blockade of autophagy with chloroquine aggravated ATRA induced apoptosis of HCC cells. Furthermore, intracellular AFP was able to complex with RAR in PLC/PRF/5 cells. Knockdown of AFP in PLC/PRF/5 cells augmented the up-regulation of ATG7 by ATRA while overexpression of AFP in HLE cells attenuated ATRA induced ATG7 expression and autophagy. Thus, ATRA induced ATG7 and autophagy participated in its cytotoxicity on HCC cells and AFP interfere with the induction of ATG7 and autophagy through forming complex with RAR.

scholarly journals UVB-mediated activation of p38 mitogen-activated protein kinase enhances resistance of normal human keratinocytes to apoptosis by stabilizing cytoplasmic p53

2002 ◽  
Vol 365 (1) ◽  
pp. 133-145 ◽  
Author(s):  
Nadine CHOUINARD ◽  
Kristoffer VALERIE ◽  
Mahmoud ROUABHIA ◽  
Jacques HUOT
Keyword(s):  
Adaptive Response ◽  
Human Keratinocytes ◽  
Dominant Negative ◽  
Mitogen Activated Protein Kinase ◽  
Dominant Negative Mutant ◽  
Normal Human Keratinocytes ◽  
Mitogen Activated Protein ◽  
Normal Human ◽  
Induced Apoptosis ◽  
Negative Mutant

Human keratinocytes respond to UV rays by developing a fast adaptive response that contributes to maintaining their functions and survival. We investigated the role of the mitogen-activated protein kinase pathways in transducing the UV signals in normal human keratinocytes. We found that UVA, UVB or UVC induced a marked and persistent activation of p38, whereas c-Jun N-terminal kinase or extracellular signal-regulated kinase were less or not activated respectively. Inhibition of p38 activity by expression of a dominant-negative mutant of p38 or with SB203580 impaired cell viability and led to an increase in UVB-induced apoptosis. This sensitization to apoptosis was independent of caspase activities. Inhibition of p38 did not sensitize transformed HaCaT keratinocytes to UVB-induced apoptosis. In normal keratinocytes, expression of a dominant-negative mutant of p53 increased UVB-induced cell death, pointing to a role for p53. In these cells, UVB triggered a p38-dependent phosphorylation of p53 on Ser-15. This phosphorylation was associated with an SB203580-sensitive accumulation of p53, even in the presence of a serine phosphatase inhibitor. Accumulated p53 was localized mainly in the cytoplasm, independently of CRM1 nuclear export. In HaCaT cells, p53 was localized exclusively in the nucleus and its distribution and level were not affected by UVB or p38 inhibition. However, UVB induced an SB203580-insensitive phosphorylation on Ser-15 of mutated p53. Overall, our results suggest that, in normal human keratinocytes, protection against UVB depends on p38-mediated phosphorylation and stabilization of p53 and is tightly associated with the cytoplasmic sequestration of wild-type p53. We conclude that the p38/p53 pathway plays a key role in the adaptive response of normal human keratinocytes against UV stress.

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