bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hyaluronan, CD44, and Emmprin Regulate Lactate Efflux and Membrane Localization of Monocarboxylate Transporters in Human Breast Carcinoma Cells
Authors: Slomiany Mark G. , Grass G. Daniel , Robertson Angela D. , Yang Xiao Y. , Maria Bernard L. , Beeson Craig , Toole Bryan P. 
Published: January 2009

Abstract
Interactions of hyaluronan with CD44 in tumor cells play important cooperative roles in various aspects of malignancy and drug resistance. Emmprin (CD147; basigin) is a cell surface glycoprotein of the immunoglobulin superfamily that is highly up-regulated in malignant cancer cells and stimulates hyaluronan production, as well as several downstream signaling pathways. Emmprin also interacts with various monocarboxylate transporters (MCT). Malignant cancer cells use the glycolytic pathway and require MCTs to efflux lactate that results from glycolysis. Glycolysis and lactate secretion contribute to malignant cell behaviors and drug resistance in tumor cells. In the present study, we find that perturbation of endogenous hyaluronan, using small hyaluronan oligosaccharides, rapidly inhibits lactate efflux from breast carcinoma cells; down-regulation of emmprin, using emmprin small interfering RNA, also results in decreased efflux. In addition, we find that CD44 coimmunoprecipitates with MCT1, MCT4, and emmprin and colocalizes with these proteins at the plasma membrane. Moreover, after treatment of the cells with hyaluronan oligosaccharides, CD44, MCT1, and MCT4 become localized intracellularly whereas emmprin remains at the cell membrane. Together, these data indicate that constitutive interactions among hyaluronan, CD44, and emmprin contribute to regulation of MCT localization and function in the plasma membrane of breast carcinoma cells. [Cancer Res 2009;69(4):1293–301]
Transcriptional Switch of Dormant Tumors to Fast-Growing Angiogenic Phenotype
Authors: Almog Nava , Ma Lili , Raychowdhury Raktima , Schwager Christian , Erber Ralf , Short Sarah , Hlatky Lynn , Vajkoczy Peter , Huber Peter E. , Folkman Judah , Abdollahi Amir 
Published: January 2009

Abstract
Tumor dormancy has important implications for early detection and treatment of cancer. Lack of experimental models and limited clinical accessibility constitute major obstacles to the molecular characterization of dormant tumors. We have developed models in which human tumors remain dormant for a prolonged period of time (&gt;120 days) until they switch to rapid growth and become strongly angiogenic. These angiogenic tumors retain their ability to grow fast once injected in new mice. We hypothesized that dormant tumors undergo a stable genetic reprogramming during their switch to the fast-growing phenotype. Genome-wide transcriptional analysis was done to dissect the molecular mechanisms underlying the switch of dormant breast carcinoma, glioblastoma, osteosarcoma, and liposarcoma tumors. A consensus expression signature distinguishing all four dormant versus switched fast-growing tumors was generated. In alignment with our phenotypic observation, the angiogenesis process was the most significantly affected functional gene category. The switch of dormant tumors was associated with down-regulation of angiogenesis inhibitor thrombospondin and decreased sensitivity of angiogenic tumors to angiostatin. The conversion of dormant tumors to exponentially growing tumors was also correlated with regulation and activation of pathways not hitherto linked to tumor dormancy process, such as endothelial cell–specific molecule-1, 5′-ecto-nucleotidase, tissue inhibitor of metalloproteinase-3, epidermal growth factor receptor, insulin-like growth factor receptor, and phosphatidylinositol 3-kinase signaling. Further, novel dormancy-specific biomarkers such as H2BK and Eph receptor A5 (EphA5) were discovered. EphA5 plasma levels in mice and mRNA levels in tumor specimens of glioma patients correlated with diseases stage. These data will be instrumental in identifying novel early cancer biomarkers and could provide a rationale for development of dormancy-promoting tumor therapy strategies. [Cancer Res 2009;69(3):836–44]
Inhibition of Class I Phosphoinositide 3-Kinase Activity Impairs Proliferation and Triggers Apoptosis in Acute Promyelocytic Leukemia without Affecting Atra-Induced Differentiation
Authors: Billottet Clotilde , Banerjee Lalita , Vanhaesebroeck Bart , Khwaja Asim 
Published: January 2009

Abstract
We have investigated the role of phosphoinositide 3-kinases (PI3Ks) in the in vitro pathophysiology of acute promyelocytic leukemia (APL) and in the response to treatment with all-trans-retinoic-acid (ATRA), utilizing a range of novel inhibitors that target individual or all catalytic class I isoforms of PI3K (p110α, p110β, p110δ, and p110γ). ATRA-induced phosphorylation of the Akt kinase and ribosomal S6 protein in APL cells was sensitive to class I PI3K, and p110β or p110δ inhibitors, and to the mammalian target of rapamycin (mTOR) inhibitor rapamycin. In primary APL, inhibition of p110β or p110δ triggered apoptosis in the absence or presence of ATRA. Class I PI3K inhibition could also reverse ATRA-induced protection of these cells against doxorubicin and arsenic trioxide, correlating with impaired induction of the antiapoptotic MCL-1 protein. The differentiation-inducing effects of ATRA were not dependent on class I PI3K/mTOR. In summary, class I PI3K signaling, mediated by p110β and p110δ, plays an important role in basal and ATRA-induced cell survival mechanisms in APL. Addition of PI3K inhibitors to induction treatment regimens may provide therapeutic benefit. [Cancer Res 2009;69(3):1027–36]
Proteasome Inhibition Blocks Ligand-Induced Dynamic Processing and Internalization of Epidermal Growth Factor Receptor via Altered Receptor Ubiquitination and Phosphorylation
Authors: Kesarwala Aparna H. , Samrakandi Mustapha M. , Piwnica-Worms David 
Published: January 2009

Abstract
Epidermal growth factor (EGF) receptor (EGFR), a member of the EGF superfamily of receptor tyrosine kinases, is a critical regulator of cell growth and an important target for single agent and combination anticancer therapeutics. To further investigate the dynamics of ligand-induced EGFR processing and regulation noninvasively, we developed a chimeric EGFR-firefly luciferase (FLuc) fusion reporter to directly monitor processing of EGFR in real-time. In a stable HeLa cell line expressing the reporter at physiologically relevant levels, bioluminescence imaging continuously monitored reporter dynamics, correlating with the ligand-induced response of endogenous EGFR as determined by Western blot, subcellular localization of an EGFR-green fluorescent protein (GFP) fusion protein, and validated pharmacologic responses. The signaling competency of the reporter was confirmed by gene rescue experiments in EGFR-null cells. Bioluminescence analysis further showed that proteasome inhibition with bortezomib or MG132 attenuated overall ligand-induced degradation of EGFR. In cells expressing EGFR-GFP, pretreatment with proteasome inhibitors trapped essentially all of the receptor at the cell membrane both before and after ligand-induced activation with EGF. Furthermore, proteasome inhibition enhanced receptor ubiquitination in both the basal and ligand-activated states as well as delayed the processing of ligand-activated phosphorylation of the receptor, kinetically correlating with attenuated receptor degradation. These observations point to a potential mechanism for the synergistic therapeutic effects of combination EGFR- and proteasome-targeted therapies. [Cancer Res 2009;69(3):976–83]
p21/Cip1 and p27/Kip1 Are Essential Molecular Targets of Inositol Hexaphosphate for Its Antitumor Efficacy against Prostate Cancer
Authors: Roy Srirupa , Gu Mallikarjuna , Ramasamy Kumaraguruparan , Singh Rana P. , Agarwal Chapla , Siriwardana Sunitha , Sclafani Robert A. , Agarwal Rajesh 
Published: January 2009

Abstract
Inositol hexaphosphate (IP6) causes G1 arrest and increases cyclin-dependent kinase inhibitors p21/Cip1 and p27/Kip1 protein levels in human prostate cancer (PCa) DU145 cells lacking functional p53. However, whether cyclin-dependent kinase inhibitor I induction by IP6 plays any role in its antitumor efficacy is unknown. Herein, we observed that either p21 or p27 knockdown by small interfering RNA has no considerable effect on IP6-induced G1 arrest, growth inhibition, and death in DU145 cells; however, the simultaneous knockdown of both p21 and p27 reversed the effects of IP6. To further confirm these findings both in vitro and in vivo, we generated DU145 cell variants with knockdown levels of p21 (DU-p21), p27 (DU-p27), or both (DU-p21+p27) via retroviral transduction of respective short hairpin RNAs. Knocking down p21 or p27 individually did not alter IP6-caused cell growth inhibition and G1 arrest; however, their simultaneous ablation completely reversed the effects of IP6. In tumor xenograft studies, IP6 (2% w/v, in drinking water) caused a comparable reduction in tumor volume (40–46%) and tumor cell proliferation (26–28%) in DU-EV (control), DU-p21, and DU-p27 tumors but lost most of its effect in DU-p21+p27 tumors. IP6-caused apoptosis also occurred in a Cip/Kip-dependent manner because DU-p21+p27 cells were completely resistant to IP6-induced apoptosis both in cell culture and xenograft. Together, these results provide evidence, for the first time, of the critical role of p21 and p27 in mediating the anticancer efficacy of IP6, and suggest their redundant role in the antiproliferative and proapoptotic effects of IP6 in p53-lacking human PCa cells, both in vitro and in vivo. [Cancer Res 2009;69(3):1166–73]
Akt Activation Synergizes with Trp53 Loss in Oral Epithelium to Produce a Novel Mouse Model for Head and Neck Squamous Cell Carcinoma
Authors: Moral Marta , Segrelles Carmen , Lara M. Fernanda , Martínez-Cruz Ana Belén , Lorz Corina , Santos Mirentxu , García-Escudero Ramón , Lu Jerry , Kiguchi Kaoru , Buitrago Agueda , Costa Clotilde , Saiz Cristina , Rodriguez-Peralto Jose L. , Martinez-Tello Francisco J. , Rodriguez-Pinilla Maria , Sanchez-Cespedes Montserrat , Garín Marina , Grande Teresa , Bravo Ana , DiGiovanni John , Paramio Jesús M. 
Published: January 2009

Abstract
Head and neck squamous cell carcinoma (HNSCC) is a common human neoplasia with poor prognosis and survival that frequently displays Akt overactivation. Here we show that mice displaying constitutive Akt activity (myrAkt) in combination with Trp53 loss in stratified epithelia develop oral cavity tumors that phenocopy human HNSCC. The myrAkt mice develop oral lesions, making it a possible model of human oral dysplasia. The malignant conversion of these lesions, which is hampered due to the induction of premature senescence, is achieved by the subsequent ablation of Trp53 gene in the same cells in vivo. Importantly, mouse oral tumors can be followed by in vivo imaging, show metastatic spreading to regional lymph nodes, and display activation of nuclear factor-κB and signal transducer and activator of transcription-3 pathways and decreased transforming growth factor-β type II receptor expression, thus resembling human counterparts. In addition, malignant conversion is associated with increased number of putative tumor stem cells. These data identify activation of Akt and p53 loss as a major mechanism of oral tumorigenesis in vivo and suggest that blocking these signaling pathways could have therapeutic implications for the management of HNSCC. [Cancer Res 2009;69(3):1099–108]
Retinoblastoma Tumor Suppressor Gene Expression Determines the Response to Sequential Flavopiridol and Doxorubicin Treatment in Small-Cell Lung Carcinoma
Authors: Budak-Alpdogan Tulin , Chen Bobin , Warrier Anjali , Medina Daniel J. , Moore Dirk , Bertino Joseph R. 
Published: January 2009

AbstractPurpose: Small-cell lung cancers (SCLC) are defective in many regulatory mechanisms that control cell cycle progression, i.e., functional retinoblastoma protein (pRb). Flavopiridol inhibits proliferation and induces apoptosis in SCLC cell lines. We hypothesized that the sequence flavopiridol followed by doxorubicin would be synergistic in pRb-deficient SCLC cells.Experimental Design: A H69 pRb-deficient SCLC cell line, H865, with functional pRb and H865 pRb small interfering RNA (siRNA) knockdown cells were used for in vitro and in vivo experiments. The in vivo efficiencies of various sequential combinations were tested using nude/nude athymic mice and human SCLC xenograft models.Results: Flavopiridol then doxorubicin sequential treatment was synergistic in the pRB-negative H69 cell line. By knocking down pRb with specific siRNA, H865 clones with complete pRb knockdown became sensitive to flavopiridol and doxorubicin combinations. pRb-deficient SCLC cell lines were highly sensitive to flavopiridol-induced apoptosis. pRb-positive H865 cells arrested in G0-G1 with flavopiridol exposure, whereas doxorubicin and all flavopiridol/doxorubicin combinations caused a G2-M block. In contrast, pRb-negative SCLC cells did not arrest in G0-G1 with flavopiridol exposure. Flavopiridol treatment alone did not have an in vivo antitumor effect, but sequential flavopiridol followed by doxorubicin treatment provided tumor growth control and a survival advantage in Rb-negative xenograft models, compared with the other sequential treatments.Conclusions: Flavopiridol and doxorubicin sequential treatment induces potent in vitro and in vivo synergism in pRb-negative SCLC cells and should be clinically tested in tumors lacking functional pRB.
Inhibition of Poly(ADP-Ribose) Polymerase-1 Enhances Temozolomide and Topotecan Activity against Childhood Neuroblastoma
Authors: Daniel Rachel A. , Rozanska Agata L. , Thomas Huw D. , Mulligan Evan A. , Drew Yvette , Castelbuono Deborah J. , Hostomsky Zdenek , Plummer E. Ruth , Boddy Alan V. , Tweddle Deborah A. , Curtin Nicola J. , Clifford Steven C. 
Published: January 2009

Abstract
Purpose: High-risk neuroblastoma is characterized by poor survival rates, and the development of improved therapeutic approaches is a priority. Temozolomide and topotecan show promising clinical activity against neuroblastoma. Poly(ADP-ribose) polymerase-1 (PARP-1) promotes DNA repair and cell survival following genotoxic insult; we postulated that its inhibition may enhance the efficacy of these DNA-damaging drugs in pediatric cancers.
Experimental Design: We evaluated the chemosensitizing properties of the PARP inhibitor AG014699 (Pfizer, Inc.) in combination with temozolomide and topotecan, against human neuroblastoma cells and xenografts, alongside associated pharmacologic and toxicologic indices.
Results: Addition of PARP-inhibitory concentrations of AG014699 significantly potentiated growth inhibition by both topotecan (1.5- to 2.3-fold) and temozolomide (3- to 10-fold) in vitro, with equivalent effects confirmed in clonogenic assays. In two independent in vivo models (NB1691 and SHSY5Y xenografts), temozolomide caused a xenograft growth delay, which was enhanced by co-administration of AG014699, and resulted in complete and sustained tumor regression in the majority (6 of 10; 60%) of cases. Evidence of enhanced growth delay by topotecan/AG014699 co-administration was observed in NB1691 xenografts. AG014699 metabolites distributed rapidly into the plasma (Cmax, 1.2-1.9 nmol/L at 30 min) and accumulated in xenograft tissues (Cmax, 1-2 μmol/L at 120 min), associated with a sustained suppression of PARP-1 enzyme activity. Doses of AG014699 required for potentiation were not toxic per se.
Conclusions: These data show enhancement of temozolomide and topotecan efficacy by PARP inhibition in neuroblastoma. Coupled with the acceptable pharmacokinetic, pharmacodynamic, and toxicity profiles of AG014699, our findings provide strong rationale for investigation of PARP inhibitors in pediatric early clinical studies.
Vorinostat and bortezomib exert synergistic antiproliferative and proapoptotic effects in colon cancer cell models
Authors: Pitts Todd M. , Morrow Mark , Kaufman Sara A. , Tentler John J. , Eckhardt S. Gail 
Published: January 2009

Abstract
Despite the availability of several Food and Drug Administration-approved drugs, advanced inoperable colorectal cancer remains incurable. In this study, we focused on the development of combined molecular targeted therapies against colon cancer by testing the efficacy of the combination of the histone deacetylase inhibitor vorinostat with the proteasome inhibitor bortezomib to determine if this resulted in synergistic antitumor effects against colorectal cancer. The effects of the histone deacetylase inhibitor vorinostat in combination with the proteasome inhibitor bortezomib on the growth of two colorectal cancer cell lines were assessed with regard to proliferation, cell cycle arrest, and apoptosis. Treatment with the combination of vorinostat and bortezomib resulted in a synergistic decrease in proliferation of both colorectal cancer cell lines compared with treatment with single agents alone. This inhibition was associated with a synergistic increase in apoptosis as measured by caspase-3/7 activity and cleaved poly(ADP-ribose) polymerase. In addition, we observed an increase in the proapoptotic protein BIM and in the number of cells arrested in the G2-M phase of the cell cycle. Although p21 levels were significantly increased, short hairpin RNA knockdown of p21 did not lead to changes in proliferation in response to the combination of drugs, indicating that although p21 is a target of these drugs, it is not required to mediate their antiproliferative effects. These data indicate that combination treatment with vorinostat and bortezomib result in synergistic antiproliferative and proapoptotic effects against colon cancer cell lines, providing a rational basis for the clinical use of this combination for the treatment of colorectal cancer. [Mol Cancer Ther 2009;8(2):342–9]
WIF1, a Wnt pathway inhibitor, regulates SKP2 and c-myc expression leading to G1 arrest and growth inhibition of human invasive urinary bladder cancer cells
Authors: Tang Yaxiong , Simoneau Anne R. , Liao Wu-xiang , Yi Guo , Hope Christopher , Liu Feng , Li Shunqiang , Xie Jun , Holcombe Randall F. , Jurnak Frances A. , Mercola Dan , Hoang Bang H. , Zi Xiaolin 
Published: January 2009

Abstract
Epigenetic silencing of secreted wingless-type (Wnt) antagonists through hypermethylation is associated with tobacco smoking and with invasive bladder cancer. The secreted Wnt inhibitory factor-1 (WIF1) has shown consistent growth-inhibitory effect on various cancer cell lines. Therefore, we assessed the mechanisms of action of WIF1 by either restoring WIF1 expression in invasive bladder cancer cell lines (T24 and TSU-PR1) or using a recombinant protein containing functional WIF1 domain. Both ectopic expression of WIF1 and treatment with WIF1 domain protein resulted in cell growth inhibition via G1 arrest. The G1 arrest induced by WIF1 is associated with down-regulation of SKP2 and c-myc and up-regulation of p21/WAF1 and p27/Kip1. Conversely, reexpression of SKP2 in WIF1-overexpressing TSU-PR1 cells attenuated the WIF1-induced G1 arrest. Furthermore, inhibition of nuclear Wnt signaling by either dominant-negative LEF1 or short hairpin RNA of TCF4 also reduced SKP2 expression. The human SKP2 gene contains two TCF/LEF1 consensus binding sites within the promoter. Chromatin immunoprecipitation/real-time PCR analysis revealed that both WIF1 and dominant-negative LEF1 expression decreased the in vivo binding of TCF4 and β-catenin to the SKP2 promoter. Together, our results suggest that mechanisms of WIF1-induced G1 arrest include (a) SKP2 down-regulation leading to p27/Kip1 accumulation and (b) c-myc down-regulation releasing p21/WAF1 transcription. Additionally, we show that WIF1 inhibits in vivo bladder tumor growth in nude mice. These observations suggest a mechanism for transformation of bladder epithelium on loss of WIF1 function and provide new targets such as SKP2 for intervention in WIF1-deficient bladder cancer. [Mol Cancer Ther 2009;8(2):458–68]
Discovery of Ixabepilone
Authors: Hunt John T. 
Published: January 2009

Abstract
The discovery of the antineoplastic agent paclitaxel and its unique activity as a microtubule-stabilizing agent resulted in dramatic improvements in the treatment of breast, ovarian, and non-small cell lung cancers. Despite the potent antitumor activity of taxanes such as paclitaxel, efficacy of these agents has been limited by development of taxane-resistant tumors in patients. This review describes, with some historical context, our successful efforts to discover a next-generation microtubule-stabilizing agent for the treatment of cancer. In collaboration with the Gesellschaft für Biotechnologische Forschung, we evaluated the epothilones, originally isolated from the myxobacterium Sorangium cellulosum, as potential anticancer agents. Experiments performed at Bristol-Myers Squibb confirmed the ability of these agents to induce tubulin polymerization, cell cycle arrest, and apoptosis. Epothilones A and B showed potent cytotoxic activity toward paclitaxel-sensitive and paclitaxel-resistant cells expressing P-glycoprotein or mutant tubulin. Because the parent epothilones were subject to inactivation via esterase cleavage, we used semisynthetic approaches to prepare analogues without this liability. BMS-247550 (ixabepilone), the lactam analogue of epothilone B, showed increased metabolic stability, potent tubulin polymerization activity, and retained activity against paclitaxel-resistant lines. Based on its shown efficacy in clinical trials, ixabepilone was approved by the Food and Drug Administration in 2007 for treatment of drug-resistant/refractory metastatic or locally advanced breast cancer. [Mol Cancer Ther 2009;8(2):275–81]
REV1 Is Implicated in the Development of Carcinogen-Induced Lung Cancer
Authors: Dumstorf Chad A. , Mukhopadhyay Suparna , Krishnan Elangovan , Haribabu Bodduluri , McGregor W. Glenn 
Published: January 2009

Abstract
The somatic mutation hypothesis of cancer predicts that reducing the frequency of mutations induced by carcinogens will reduce the incidence of cancer. To examine this, we developed an antimutator strategy based on the manipulation of the level of a protein required for mutagenic bypass of DNA damage induced by the ubiquitous carcinogen benzo[a]pyrene. The expression of this protein, REV1, was reduced in mouse cells using a vector encoding a gene-specific targeting ribozyme. In the latter cells, mutagenesis induced by the activated form of benzo[a]pyrene was reduced by &gt;90%. To examine if REV1 transcripts could be lowered in vivo, the plasmid was complexed with polyethyleneimine, a nonviral cationic polymer, and delivered to the lung via aerosol. The endogenous REV1 transcript in the bronchial epithelium as determined by quantitative real-time PCR in laser capture microdissected cells was reduced by 60%. There was a significant decrease in the multiplicity of carcinogen-induced lung tumors from 6.4 to 3.7 tumors per mouse. Additionally, REV1 inhibition completely abolished tumor formation in 27% of the carcinogen-exposed mice. These data support the central role of the translesion synthesis pathway in the development of lung cancer. Further, the selective modulation of members of this pathway presents novel potential targets for cancer prevention. The somatic mutation hypothesis of cancer predicts that the frequency of cancers will also be reduced. (Mol Cancer Res 2009;7(2):247–54)