bluuebunny/crossref_metadata_2025_split huggingface dataset:
Darbepoietin Alfa Potentiates the Efficacy of Radiation Therapy in Mice with Corrected or Uncorrected Anemia
Authors: Ning Shoucheng , Hartley Cynthia , Molineux Graham , Knox Susan J. 
Published: June 2022

Abstract
Darbepoietin alfa (DA) is a long-acting analogue of erythropoietin that has reduced receptor affinity and enhanced biological activity. Experiments were done to test the hypothesis that correction of anemia in tumor-bearing mice by DA would increase tumor oxygenation and potentiate radiation-induced tumor cell killing. A SCC VII tumor model was used to study tumor responses to fractionated radiation therapy in mice with anemia induced by total body irradiation. Administration of DA reduced the extent and duration of anemia and associated tumor hypoxia, protected the bone marrow cells and prevented the body weight loss from the effect of irradiation, and facilitated the recovery in a time-dependent manner, with the administration of DA prior to total body irradiation having the greatest protective effect. When combined with fractionated radiation therapy, DA increased the tumor growth delay time from 2.7 days for irradiation alone to 7.3 to 10.6 days for combination of DA and irradiation. The effect of DA on tumor responses to fractionated radiation therapy was observed when DA was given 18 to 4 days before starting radiation therapy, but DA was also equally effective as a radiosensitizer when given only 2 hours before fractionated irradiation therapy. Weekly dosing of DA was as efficacious for the enhancement of radiation responses of tumors as biweekly dosing. Similar results were obtained in the RIF-1 fibrosarcoma tumor model. These studies show that DA can effectively correct anemia in tumor-bearing mice and sensitize tumor cells to fractionated radiation therapy. Importantly, DA was also able to sensitize tumors to radiation in mice with uncorrected anemia and hypoxia, suggesting that the effect of DA on radiosensitivity was independent of these factors and a different mechanism of action may be responsible for this effect.
Association of Fetal Hormone Levels with Stem Cell Potential: Evidence for Early Life Roots of Human Cancer
Authors: Baik Inkyung , DeVito William J. , Ballen Karen , Becker Pamela S. , Okulicz William , Liu Qin , Delpapa Ellen , Lagiou Pagona , Sturgeon Susan , Trichopoulos Dimitrios , Quesenberry Peter J. , Hsieh Chung-Cheng 
Published: June 2022

Abstract
Intrauterine and perinatal factors have been linked to risk of childhood leukemia, testicular cancer, and breast cancer in the offspring. The pool of stem cells in target tissue has been suggested as a critical factor linking early life exposures to cancer. We examined the relation between intrauterine hormone levels and measurements of stem cell potential in umbilical cord blood. Cord blood donors were 40 women, ages ≥18 years, who delivered, from August 2002 to June 2003, a singleton birth after a gestation of at least 37 weeks. We assayed plasma concentrations of estradiol, unconjugated estriol, testosterone, progesterone, prolactin, sex hormone binding globulin, insulin-like growth factor-I (IGF-I), and IGF binding protein-3. For stem cell potential, we measured concentrations of CD34+ and CD34+CD38− cells and granulocyte-macrophage colony-forming unit (CFU-GM). We applied linear regression analysis and controlled for maternal and neonatal characteristics. We found strong positive associations between IGF-I and stem cell measures, 1 SD increase in IGF-I being associated with a 41% increase in CD34+ (P = 0.008), a 109% increase in CD34+CD38− (P = 0.005), and a 94% increase in CFU-GM (P = 0.01). Similar associations were observed for IGF binding protein-3. Among steroid hormones, estriol and testosterone were significantly positively associated with CD34+ and CFU-GM. These findings indicate that levels of growth factors and hormones are strongly associated with stem cell potential in human umbilical cord blood and point to a potential mechanism that may mediate the relationship between in utero exposure to hormones and cancer risk in the offspring.
Inhibition of Nuclear Translocation of Nuclear Factor-κB Contributes to 3,3′-Diindolylmethane-Induced Apoptosis in Breast Cancer Cells
Authors: Rahman KM Wahidur , Sarkar Fazlul H. 
Published: June 2022

AbstractDietary indole-3-carbinol (I3C), a natural compound present in vegetables of the genus Brassica, showed clinical benefits and caused apoptosis in breast cancer cells. Our laboratory and others have shown that I3C induces apoptosis in breast cancer cells mediated by inactivation of Akt and nuclear factor-κB (NF-κB) pathway. 3,3′-Diindolylmethane (DIM), a major in vivo acid-catalyzed condensation product of I3C, also showed some benefit in breast cancer. However, the precise molecular mechanism(s) by which DIM induces apoptosis in breast cancer cells has not been fully elucidated. Hence, we investigated whether DIM-induced apoptosis of breast cancer cells could also be mediated by inactivation of Akt and NF-κB. We found that DIM induces apoptotic processes in MCF10A derived malignant (MCF10CA1a) cell lines but not in nontumorigenic parental MCF10A cells. DIM specifically inhibits Akt kinase activity and abrogates the epidermal growth factor–induced activation of Akt in breast cancer cells, similar to those observed for I3C. We also found that DIM reduces phosphorylation of IκBα, an inhibitor of NF-κB. Our confocal microscopy study clearly showed that DIM blocks the translocation of p65, a subunit of NF-κB to the nucleus. DNA binding analysis and transfection studies with IκB kinase cDNA revealed that overexpression of IκB kinase mediates IκBα phosphorylation, which activates NF-κB, and this activation was completely abrogated by DIM treatment. Taken together, these results showed for the first time that the inactivation of Akt and NF-κB activity also plays important roles in DIM-induced apoptosis in breast cancer cells, which seems to be more relevant to in vivo situations.
Differential Role of Transcription-Coupled Repair in UVB–Induced Response of Human Fibroblasts and Keratinocytes
Authors: D'Errico Mariarosaria , Teson Massimo , Calcagnile Angelo , Nardo Tiziana , De Luca Naomi , Lazzari Chiara , Soddu Silvia , Zambruno Giovanna , Stefanini Miria , Dogliotti Eugenia 
Published: June 2022

Abstract
Most solar radiation–induced skin cancers arise in keratinocytes. In the human epidermis, protection against cancer is thought to be mediated mainly by nucleotide excision repair (NER) of UVB-induced cyclobutane pyrimidine dimers, and by elimination of the damaged cells by apoptosis. NER consists of two subpathways: global genome repair (GGR) and transcription-coupled repair (TCR). Here, we investigate the impact of defects in NER subpathways on the cellular response to UVB-induced damage by comparing primary human keratinocytes and fibroblasts from normal, XP-C (GGR-defective), and CS-A (TCR-defective) individuals. We show that human keratinocytes are more resistant to UVB killing than fibroblasts and present higher levels of UVB-induced DNA repair synthesis due to a more efficient GGR. The CS-A defect is associated with a strong apoptotic response in fibroblasts but not in keratinocytes. Following an UVB dose of 1,000 J/m2, no p53-mediated transactivation of mdm2 is observed in CS-A fibroblasts, whereas the p53-mdm2 circuit is fully activated in CS-A keratinocytes. Thus, in fibroblasts, the signal for apoptosis originates from DNA photoproducts in the transcribed strand of active genes, whereas in keratinocytes, it is largely TCR-independent. This study shows that the response to UVB radiation is cell type–specific in humans and provides the first evidence that a deficiency in TCR has a different impact depending on the cell type. These findings have important implications for the mechanism of skin cancer protection after UVB damage and may explain the lack of skin cancer in patients with Cockayne syndrome.
Activation of the β-Catenin/T-Cell–Specific Transcription Factor/Lymphoid Enhancer Factor-1 Pathway by Plasminogen Activators in ECV304 Carcinoma Cells
Authors: Maupas-Schwalm Françoise , Robinet Catherine , Augé Nathalie , Thiers Jean-Claude , Garcia Virginie , Cambus Jean-Pierre , Salvayre Robert , Nègre-Salvayre Anne 
Published: June 2022

Abstract
Besides its involvement in clot lysis, the plasminogen activator (PA) system elicits various cellular responses involved in cell migration, adhesion, and proliferation and plays a key role in the progression of cancers. β-Catenin interacts with E-cadherins and functions as transcriptional coactivator of the Wnt-signaling pathway, which is implicated in tumor formation when aberrantly activated. We report that tissue-type plasminogen activator (tPA) elicited tyrosine phosphorylation and cytosolic accumulation of an active (non–serine-threonin phosphorylated, nonubiquitinated) form of β-catenin in ECV304 carcinoma cells. tPA-dependent β-catenin activation is mediated through epidermal growth factor receptor (EGFR) transactivation (via Src), suggested by the inhibitory effects of AG1478 and PP2 (specific inhibitors of EGFR and Src, respectively) and by the lack of β-catenin activation in EGFR-negative B82 fibroblasts. EGFR phosphorylation and β-catenin activation were inhibited by plasminogen activator inhibitor 1 and pertussis toxin, two inhibitors of the urokinase-type plasminogen activator (uPA)/uPA receptor system. β-Catenin activation was correlated with the phosphorylation of glycogen synthase kinase-3β through a phosphatidylinositol 3-kinase/Akt-dependent mechanism. Gel shift experiments revealed the activation of β-catenin/T-cell–specific transcription factor (Tcf)/lymphoid enhancer factor-1 (Lef) transcriptional complex, evidenced by an increased binding of nuclear extracts to oligonucleotides containing the cyclin D1 Lef/Tcf site. β-Catenin silencing through small interfering RNA and antisense oligonucleotides inhibited both the tPA-mediated cyclin D1 expression and cell proliferation. A similar activation of the β-catenin pathway was triggered by amino-terminal fragment, the NH2-terminal catalytically inactive fragment of tPA, thus suggesting that this effect was independent of the proteolytic activity of plasminogen activators. In conclusion, the β-catenin/Lef/Tcf pathway is activated by tPA and is involved in cell cycle progression and proliferation.
Alendronate Inhibits Intraperitoneal Dissemination in In vivo Ovarian Cancer Model
Authors: Hashimoto Kae , Morishige Ken-ichirou , Sawada Kenjiro , Tahara Masahiro , Kawagishi Rikako , Ikebuchi Yoshihide , Sakata Masahiro , Tasaka Keiichi , Murata Yuji 
Published: June 2022

Abstract
Ovarian cancer is characterized by diffuse peritoneal carcinomatosis and often by large volumes of ascites. We previously reported that alendronate, a nitrogen-containing bisphosphonate, inhibited ovarian cancer cell migration by attenuating the activation of Rho through inhibiting the mevalonate pathway. However, questions remain about the ability of alendronate to inhibit the invasiveness of cancer cells to the adherent tissues and the growth of disseminated ovarian cancer in vivo. We established an in vivo ovarian cancer model with i.p. carcinomatosis in athymic immunodeficient mice. In the prevention model, in which alendronate administration started from the day after tumor inoculation, alendronate prevented the stromal invasion, reduced the tumor burden, and inhibited ascites accumulation. Histologic observation revealed that alendronate treatment decreased the stromal invasion of the i.p. tumor while inhibiting the metalloproteinase-2 activity in ascites. This antitumor effect might result from the inhibition of cancer cell migration and proteolytic activity. In the treatment model, in which alendronate was given from 10 days after tumor inoculation when macroscopic tumors are already implanted in the peritoneum, the antitumor effect was weaker but still significant. Furthermore, alendronate administration decreased the serum CA-125 levels of mice bearing disseminated ovarian cancer compared with those of nontreated mice. The potent effects of alendronate in reducing stromal invasion, tumor burden, and ascites suggest that it will be of value in regimens for treatment of women with ovarian cancer.
Effects of Hypoxia on Radiation-Responsive Stress-Activated Protein Kinase, p53, and Caspase 3 Signals in TK6 Human Lymphoblastoid Cells
Authors: Samuni Ayelet M. , Kasid Usha , Chuang Eric Y. , Suy Simeng , DeGraff William , Krishna Murali C. , Russo Angelo , Mitchell James B. 
Published: June 2022

Abstract
Despite significant evidence of a role of hypoxia in cellular resistance to ionizing radiation–induced toxicity, the underlying molecular mechanisms remain unclear. This study focused on the influence of hypoxia on radiation-induced signals in TK6 human lymphoblastoid cells. Hypoxic (&lt;10 ppm oxygen) and aerobic cells were exposed to equilethal doses of ionizing radiation, radiation dose ratio, 3:1 (hypoxia:air). Hypoxia alone or radiation treatment under aerobic or hypoxic conditions led to increased levels of phospho-p44/42 mitogen-activated protein kinase. Levels of phospho-p38 mitogen-activated protein kinase did not change as a result of either hypoxia or irradiation. Hypoxia alone had no effect on expression of phospho-stress-activated protein kinase (SAPK), wild-type p53, or cleaved caspase 3. Irradiation under aerobic conditions resulted in an increase in the phospho-SAPK signal, whereas hypoxia suppressed the irradiation-induced increase in the level of phospho-SAPK. Both hypoxic and aerobic cells showed increases in p53 levels in response to radiation. Hypoxia blocked radiation-induced cleavage of caspase 3 and poly-ADP-ribose polymerase. Irradiation of aerobic and hypoxic TK6 cells using 6 and 18 Gy, respectively, resulted in a similar and significant increase in fraction of apoptotic cells within 24 hours postirradiation. In contrast, basal levels of apoptosis were observed at 24 hours postirradiation in aerobic and hypoxic NH32 cells, a p53 null derivative of TK6 cells. These results suggest that radiation-induced apoptosis under hypoxia occurs independent of phospho-SAPK and caspase 3, and the p53 response is an obligatory apoptotic signal in TK6 cells.
Retinoic Acid Inhibits the Proliferative Response Induced by CD40 Activation and Interleukin-4 in Mantle Cell Lymphoma
Authors: Guidoboni Massimo , Zancai Paola , Cariati Roberta , Rizzo Silvana , Dal Col Jessica , Pavan Alessandro , Gloghini Annunziata , Spina Michele , Cuneo Antonio , Pomponi Fabrizio , Bononi Antonio , Doglioni Claudio , Maestro Roberta , Carbone Antonino , Boiocchi Mauro , Dolcetti Riccardo 
Published: June 2022

AbstractMantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin's lymphoma with poor response to therapy and unfavorable prognosis. Here, we show that retinoic acid (RA) isomers significantly inhibit the proliferation of both primary MCL cultures (n = 7) and established cell lines (Granta 519 and SP-53) as shown by [3H]thymidine uptake and carboxyfluorescein diacetate succinimidyl ester labeling coupled with cyclin D1 staining. RA induces cell accumulation in G0-G1 together with a marked up-regulation of p27Kip1 by inhibiting ubiquitination and proteasome-dependent degradation of the protein. The p21Cip1 inhibitor was also up-regulated by RA in Granta 519 cells, whereas the expression of cyclin D1 is unaffected. Most of RA-induced p27Kip1 was bound to cyclin D1/cyclin-dependent kinase 4 complexes, probably contributing to the decreased cyclin-dependent kinase 4 kinase activity and pRb hypophosphorylation observed in RA-treated cells. Experiments with receptor-selective ligands indicate that RA receptor α cooperates with retinoid X receptors in mediating RA-dependent MCL cell growth inhibition. Notably, RA isomers, and particularly 9-cis-RA, also inhibited the growth-promoting effect induced in primary MCL cells by CD40 activation alone or in combination with interleukin-4. Immunohistochemical analysis showed that significant numbers of CD40L-expressing lymphoid cells are present in lymph node biopsies of MCL patients. These results therefore further strengthen the possibility that triggering of CD40 by infiltrating CD40L+ cells may continuously promote the growth of MCL cells in vivo. On these grounds, our findings that RA inhibits basal MCL proliferation as well as MCL growth-promoting effects exerted by microenvironmental factors make these compounds highly attractive in terms of potential clinical efficacy in this setting.
Inhibition of Glycolysis in Cancer Cells: A Novel Strategy to Overcome Drug Resistance Associated with Mitochondrial Respiratory Defect and Hypoxia
Authors: Xu Rui-hua , Pelicano Helene , Zhou Yan , Carew Jennifer S. , Feng Li , Bhalla Kapil N. , Keating Michael J. , Huang Peng 
Published: June 2022

Abstract
Cancer cells generally exhibit increased glycolysis for ATP generation (the Warburg effect) due in part to mitochondrial respiration injury and hypoxia, which are frequently associated with resistance to therapeutic agents. Here, we report that inhibition of glycolysis severely depletes ATP in cancer cells, especially in clones of cancer cells with mitochondrial respiration defects, and leads to rapid dephosphorylation of the glycolysis-apoptosis integrating molecule BAD at Ser112, relocalization of BAX to mitochondria, and massive cell death. Importantly, inhibition of glycolysis effectively kills colon cancer cells and lymphoma cells in a hypoxic environment in which the cancer cells exhibit high glycolytic activity and decreased sensitivity to common anticancer agents. Depletion of ATP by glycolytic inhibition also potently induced apoptosis in multidrug-resistant cells, suggesting that deprivation of cellular energy supply may be an effective way to overcome multidrug resistance. Our study shows a promising therapeutic strategy to effectively kill cancer cells and overcome drug resistance. Because the Warburg effect and hypoxia are frequently seen in human cancers, these findings may have broad clinical implications.
Interactions between Prostaglandin E2, Liver Receptor Homologue-1, and Aromatase in Breast Cancer
Authors: Zhou Jiong , Suzuki Takashi , Kovacic Agnes , Saito Ryoko , Miki Yasuhiro , Ishida Takanori , Moriya Takuya , Simpson Evan R. , Sasano Hironobu , Clyne Colin D. 
Published: June 2022

Abstract
Local synthesis of estrogens within breast adipose tissue by cytochrome P450 aromatase contributes to the growth of postmenopausal breast cancers. One of the major stimulators of aromatase expression in breast is prostaglandin E2 (PGE2) derived from tumorous epithelium and/or infiltrating macrophages. Recently, the orphan nuclear receptor, liver receptor homologue-1 (LRH-1), has also been shown to regulate aromatase expression in breast adipose tissue. We therefore examined the expression of, and correlations between, aromatase and LRH-1 mRNA in a panel of breast carcinoma tissues and adjacent adipose tissue. LRH-1 mRNA expression was low in normal breast tissue but markedly elevated in both breast carcinoma tissue and adipose tissue surrounding the tumor invasion (thereby paralleling aromatase expression). Laser capture microdissection localized the site of LRH-1 expression to tumor epithelial cells but not to intratumoral stromal cells. A strong correlation between LRH-1 and aromatase mRNA levels was observed in tumor-containing adipose tissue but not in tumor tissue. Ectopic expression of LRH-1 in primary human adipose stromal cells strongly activated endogenous aromatase mRNA expression and enzyme activity. Finally, treatment of adipose stromal cells with PGE2 induced expression of both LRH-1 and aromatase. We suggest that PGE2 derived from breast tumor tissue may increase aromatase expression in the surrounding adipose stroma in part by inducing LRH-1 in these cells. The roles of LRH-1 in breast cancer proliferation merit further study.
Genomic Amplification of Orthodenticle Homologue 2 in Medulloblastomas
Authors: Boon Kathy , Eberhart Charles G. , Riggins Gregory J. 
Published: June 2022

Abstract
To better understand the genetic basis of medulloblastoma development, we sought genomic amplifications and deletions in these tumors using digital karyotyping in combination with expression analysis. Five medulloblastoma genomes were karyotyped by sequencing an average of 195,745 genomic DNA tags for each analysis. Tags were tallied at unique positions and mapped to the human genome to determine DNA copy numbers in high resolution along each chromosome. Genomic alterations normally associated with medulloblastomas, including MYC amplification and isochromosome 17q, were easily detected. Surprisingly, analysis of only five genomes revealed novel amplicons on chromosome 14q, one of which contained the orthodenticle homologue 2 (OTX2) homeobox gene. DNA copy number analysis showed that OTX2 had undergone genomic amplification in 2 of 11 medulloblastoma cell lines and 8 of 42 primary tumors. The three genes and a predicted open reading frame flanking OTX2 in the 14q amplicon were not amplified in at least one of the other nine amplicons, implicating OTX2 as the gene target conferring a selective advantage. The degree of OTX2 amplification ranged from 8 copies to over 50 copies of the gene. OTX2 transcript was highly and specifically expressed in medulloblastoma or developing cells. Serial analysis of gene expression of 240 different human tumors or normal tissues revealed that 96% of all 783 OTX2 transcripts sequenced were in medulloblastomas or embryonic stem cells. OTX2 functions to specify the fate of neuroectoderm in various regions of the developing brain. This developmental role is consistent with the evidence suggesting that OTX2 is a medulloblastoma oncogene.
p300 Modulates Nuclear Morphology in Prostate Cancer
Authors: Debes Jose D. , Sebo Thomas J. , Heemers Hannelore V. , Kipp Benjamin R. , Haugen De Anna L. , Lohse Christine M. , Tindall Donald J. 
Published: June 2022

Abstract
Alterations in nuclear structure distinguish cancer cells from noncancer cells. These nuclear alterations can be translated into quantifiable features by digital image analysis in a process known as quantitative nuclear morphometry. Recently, quantitative nuclear morphometry has been shown to predict metastasis and biochemical recurrence of prostate cancer. However, little is known about the cellular mechanisms underlying these nuclear morphometric changes. Alterations of nuclear matrix proteins are frequently involved in changes of nuclear structure. A number of co-activators interact with these nuclear structure–related proteins, suggesting that they might be involved in quantitative nuclear morphometry changes. We have shown previously that the transcriptional co-activator p300 is involved in prostate cancer progression. However, the ability of a transcriptional regulator like p300 to modulate nuclear morphology has not been described previously. In the present study, we show that p300 expression in prostate cancer biopsy tissue from 95 patients correlates with quantifiable nuclear alterations. Moreover, we show that transfection of p300 into prostate cancer cells in culture induces quantifiable nuclear alterations, such as diameter, perimeter, and absorbance among others, as assessed by digital image analysis. These alterations correlate individually with aggressive features in prostate cancer, such as expression of the proliferation marker Ki-67 and extraprostatic extension of the tumor. Finally, we found that transfection of p300 into prostate cancer cells specifically increases mRNA and protein levels of nuclear matrix peptides lamins A and C, suggesting that these proteins mediate the p300-induced effects. These findings reveal a new insight into the transcriptional and structural regulation of prostate cancer.