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Wang S.-H.,National Taiwan University | Lin P.-Y.,Chang Gung University | Chiu Y.-C.,Chang Gung University | Huang J.-S.,Chang Gung University | And 3 more authors.
PLoS ONE | Year: 2015

Chemo-and radiotherapy cause multiple forms of DNA damage and lead to the death of cancer cells. Inhibitors of the DNA damage response are candidate drugs for use in combination therapies to increase the efficacy of such treatments. In this study, we show that curcumin, a plant polyphenol, sensitizes budding yeast to DNA damage by counteracting the DNA damage response. Following DNA damage, the Mec1-dependent DNA damage checkpoint is inactivated and Rad52 recombinase is degraded by curcumin, which results in deficiencies in double-stand break repair. Additive effects on damage-induced apoptosis and the inhibition of damage-induced autophagy by curcumin were observed. Moreover, rpd3 mutants were found to mimic the curcumin-induced suppression of the DNA damage response. In contrast, hat1 mutants were resistant to DNA damage, and Rad52 degradation was impaired following curcumin treatment. These results indicate that the histone deacetylase inhibitor activity of curcumin is critical to DSB repair and DNA damage sensitivity. Copyright: © 2015 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Hsia C.-W.,National Chung Cheng University | Ho M.-Y.,Institute of Stem Cell and Translational Cancer Research | Shui H.-A.,Graduate Institute of Medical science | Tsai C.-B.,National Chung Cheng University | Tseng M.-J.,National Chung Cheng University
International Journal of Molecular Sciences | Year: 2015

Dermal papillae (DPs) control the formation of hair shafts. In clinical settings, colchicine (CLC) induces patients’ hair shedding. Compared to the control, the ex vivo hair fiber elongation of organ cultured vibrissa hair follicles (HFs) declined significantly after seven days of CLC treatment. The cultured DP cells (DPCs) were used as the experimental model to study the influence of CLC on the protein dynamics of DPs. CLC could alter the morphology and down-regulate the expression of alkaline phosphatase (ALP), the marker of DPC activity, and induce IκBα phosphorylation of DPCs. The proteomic results showed that CLC modulated the expression patterns (fold > 2) of 24 identified proteins, seven down-regulated and 17 up-regulated. Most of these proteins were presumably associated with protein turnover, metabolism, structure and signal transduction. Protein-protein interactions (PPI) among these proteins, established by Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, revealed that they participate in protein metabolic process, translation, and energy production. Furthermore, ubiquitin C (UbC) was © 2015 by the authors; licensee MDPI, Basel, Switzerland.

Chang Y.-J.,Taipei Medical University | Chang Y.-J.,Taipei Medical University Hospital | Li L.-T.,Institute of Stem Cell and Translational Cancer Research | Chen H.-A.,Taipei Medical University | And 5 more authors.
Tumor Biology | Year: 2014

Autophagy is a survival mechanism that is activated in response to nutrient deprivation. The link between aberrant autophagy and cancer has been increasingly recognized. Survivin, an anti-apoptotic molecule, and the autophagy pathway are correlated with therapeutic responses to cancer. However, the role of autophagy in cancer progression remains unclear. Here, we generated survivin knockdown cells (survivin-KD) by introducing a short interfering RNA (siRNA) into hepatocellular carcinoma (HCC) cells, and we observed a 20 % reduction in the survival of these survivin- KD cells, as determined by MTT assay. In addition, an increased number of stress granules, increased positive staining by acridine orange and a shift in the high side scatter (SSC) cell population in flow cytometry analysis were observed in survivin-KD cells. Furthermore, electronmicroscopy revealed an increased number of autophagosomes in survivin-KD cells compared with scrambled control cells. Finally, we treated cells with an autophagy inhibitor, 3-MA, and observed a decrease in cell survival in survivin-KD cells compared with scrambled control cells. Our study suggests that an autophagy signal may be activated after the anti-apoptotic molecule survivin is suppressed. This finding implies that autophagy may be an alternative survival pathway in HCC cells and may provide a basis for the development of new therapeutic strategies for HCC. © International Society of Oncology and BioMarkers (ISOBM) 2014.

Sonawane P.,Texas Tech University Health Sciences Center | Cho H.E.,Texas Tech University Health Sciences Center | Tagde A.,Texas Tech University Health Sciences Center | Verlekar D.,Texas Tech University Health Sciences Center | And 6 more authors.
British Journal of Pharmacology | Year: 2014

Background and Purpose Isotretinoin (13-cis-retinoic acid; 13-cRA) is a differentiation inducer used to treat minimal residual disease after myeloablative therapy for high-risk neuroblastoma. However, more than 40% of children develop recurrent disease during or after 13-cRA treatment. The plasma concentrations of 13-cRA in earlier studies were considered subtherapeutic while 4-oxo-13-cis-RA (4-oxo-13-cRA), a metabolite of 13-cRA considered by some investigators as inactive, were greater than threefold higher than 13-cRA. We sought to define the metabolic pathways of 13-cRA and investigated the anti-tumour activity of its major metabolite, 4-oxo-13-cRA. Experimental Approach Effects of 13-cRA and 4-oxo-13-cRA on human neuroblastoma cell lines were assessed by DIMSCAN and flow cytometry for cell proliferation, MYCN down-regulation by reverse transcription PCR and immunoblotting, and neurite outgrowth by confocal microscopy. 13-cRA metabolism was determined using tandem MS in human liver microsomes and in patient samples. Key Results Six major metabolites of 13-cRA were identified in patient samples. Of these, 4-oxo-13-cRA was the most abundant, and 4-oxo-13-cRA glucuronide was also detected at a higher level in patients. CYP3A4 was shown to play a major role in catalysing 13-cRA to 4-oxo-13-cRA. In human neuroblastoma cell lines, 4-oxo-13-cRA and 13-cRA were equi-effective at inducing neurite outgrowth, inhibiting proliferation, decreasing MYCN mRNA and protein, and increasing the expression of retinoic acid receptor-β mRNA and protein levels. Conclusions and Implications We showed that 4-oxo-13-cRA is as active as 13-cRA against neuroblastoma cell lines. Plasma levels of both 13-cRA and 4-oxo-13-cRA should be evaluated in pharmacokinetic studies of isotretinoin in neuroblastoma. © 2014 The British Pharmacological Society.

Barnhill L.M.,University of California at San Diego | Williams R.T.,University of California at San Diego | Cohen O.,University of California at San Diego | Kim Y.,University of California at San Diego | And 9 more authors.
Cancer Research | Year: 2014

Neuroblastoma is a pediatric cancer with significant genomic and biologic heterogeneity. p16 and ARF, two important tumor-suppressor genes on chromosome 9p21, are inactivated commonly in most cancers, but paradoxically overexpressed in neuroblastoma. Here, we report that exon g in p16 is also part of an undescribed long noncoding RNA (lncRNA) that we have termed CAI2 (CDKN2A/ARF Intron 2 lncRNA). CAI2 is a single-exon gene with a poly A signal located in but independent of the p16/ARF exon 3. CAI2 is expressed at very low levels in normal tissue, but is highly expressed in most tumor cell lines with an intact 9p21 locus. Concordant expression of CAI2 with p16 and ARF in normal tissue along with the ability of CAI2 to induce p16 expression suggested that CAI2 may regulate p16 and/or ARF. In neuroblastoma cells transformed by serial passage in vitro, leading to more rapid proliferation, CAI2, p16, and ARF expression all increased dramatically. A similar relationship was also observed in primary neuroblastomas where CAI2 expression was significantly higher in advanced-stage neuroblastoma, independently of MYCN amplification. Consistent with its association with high-risk disease, CAI2 expression was also signi ficantly associated with poor clinical outcomes, although this effect was reduced when adjusted for MYCN amplification. Taken together, our findings suggested that CAI2 contributes to the paradoxical overexpression of p16 in neuroblastoma, where CAI2 may offer a useful biomarker of high-risk disease. ©2014 AACR.

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