bluuebunny/crossref_metadata_2025_split huggingface dataset:
Glucose-regulated protein 78 regulates multiple malignant phenotypes in head and neck cancer and may serve as a molecular target of therapeutic intervention
Authors: Chiu Ching-Chi , Lin Chien-Yu , Lee Li-Yu , Chen Yin-Ju , Kuo Ting-Fang , Chang Joseph Tung-Chieh , Liao Chun-Ta , Wang Hung-Ming , Yen Tzu-Chen , Shen Chia-Rui , Liao Shuen-Kuei , Cheng Ann-Joy 
Published: September 2008

Abstract
Glucose-regulated protein 78 (Grp78) is an endoplasmic reticulum chaperone protein and is overexpressed in various cancers. However, it is unclear how significance of this molecule play an active role contributing to the oncogenic effect of head and neck cancer (HNC). To investigate the potential function of Grp78, six HNC cell lines were used. We found that Grp78 is highly expressed in all six cell lines and many of the proteins were localized in the periphery regions, implying other function of this molecule aside from endoplasmic reticulum stress response. Knockdown of Grp78 by small interfering RNA significantly reduced cell growth and colony formation to 53% to 12% compared with that of controls in all six HNC cell lines. Using in vitro wound healing and Matrigel invasion assays, we found that cell migration and invasive ability were also inhibited to 23% to 2% in all these cell lines tested. In vivo xenograft studies showed that administration of Grp78-small interfering RNA plasmid into HNC xenografts significantly inhibited both tumor growth in situ (&gt;60% inhibition at day 34) and liver metastasis (&gt;90% inhibition at day 20). Our study showed that Grp78 actively regulates multiple malignant phenotypes, including cell growth, migration, and invasion. Because knockdown Grp78 expression succeeds in the reduction of tumor growth and metastatic potential, this molecule may serve as a molecular target of therapeutic intervention for HNC. [Mol Cancer Ther 2008;7(9):2788–97]
Peroxisome proliferator-activated receptor ligand MCC-555 suppresses intestinal polyps in ApcMin/+ mice via extracellular signal-regulated kinase and peroxisome proliferator-activated receptor-dependent pathways
Authors: Yamaguchi Kiyoshi , Cekanova Maria , McEntee Michael F. , Yoon Joo-Heon , Fischer Susan M. , Renes Ingrid B. , Van Seuningen Isabelle , Baek Seung Joon 
Published: September 2008

Abstract
A large body of studies has suggested that peroxisome proliferator-activated receptor γ (PPARγ) ligands, such as thiazolidinedione, are potent candidates for chemopreventive agents. MCC-555 is a PPARγ/α dual agonist and has been shown previously to induce apoptosis in vitro; however, the molecular mechanisms by which MCC-555 affects antitumorigenesis in vivo are poorly understood. In this study, we explored the antitumorigenic effects of MCC-555 both in cell culture and in Apc-deficient mice, an animal model for human familial adenomatous polyposis. MCC-555 increased MUC2 expression in colorectal and lung cancer cells, and treatment with the PPARγ antagonist GW9662 revealed that MUC2 induction by MCC-555 was mediated in a PPARγ-dependent manner. Moreover, MCC-555 increased transcriptional activity of human and mouse MUC2 promoters. Subsequently, treatment with MCC-555 (30 mg/kg/d) for 4 weeks reduced the number of small intestinal polyps to 54.8% of that in control mice. In agreement with in vitro studies, enhanced Muc2 expression was observed in the small intestinal tumors of Min mice treated with MCC-555, suggesting that MUC2 expression may be associated at least in part with the antitumorigenic action of MCC-555. In addition, highly phosphorylated extracellular signal-regulated kinase (ERK) was found in the intestinal tumors of MCC-555-treated Min mice, and inhibition of the ERK pathway by a specific inhibitor markedly suppressed MCC-555-induced Muc2 expression in vitro. Overall, these results indicate that MCC-555 has a potent tumor suppressor activity in intestinal tumorigenesis, likely involving MUC2 up-regulation by ERK and PPARγ pathways. [Mol Cancer Ther 2008;7(9):2779–87]
Targeting a metalloprotease-PAR1 signaling system with cell-penetrating pepducins inhibits angiogenesis, ascites, and progression of ovarian cancer
Authors: Agarwal Anika , Covic Lidija , Sevigny Leila M. , Kaneider Nicole C. , Lazarides Katherine , Azabdaftari Gissou , Sharifi Sheida , Kuliopulos Athan 
Published: September 2008

Abstract
Gene chip and proteomic analyses of tumors and stromal tissue has led to the identification of dozens of candidate tumor and host components potentially involved in tumor-stromal interactions, angiogenesis, and progression of invasive disease. In particular, matrix metalloproteases (MMP) have emerged as important biomarkers and prognostic factors for invasive and metastatic cancers. From an initial screen of benign versus malignant patient fluids, we delineated a metalloprotease cascade comprising MMP-14, MMP-9, and MMP-1 that culminates in activation of PAR1, a G protein-coupled protease-activated receptor up-regulated in diverse cancers. In xenograft models of advanced peritoneal ovarian cancer, PAR1-dependent angiogenesis, ascites formation, and metastasis were effectively inhibited by i.p. administration of cell-penetrating pepducins based on the intracellular loops of PAR1. These data provide an in vivo proof-of-concept that targeting the metalloprotease-PAR1 signaling system may be a novel therapeutic approach in the treatment of ovarian cancer. [Mol Cancer Ther 2008;7(9):2746–57]
1α,25-Dihydroxyvitamin D3 potentiates cisplatin antitumor activity by p73 induction in a squamous cell carcinoma model
Authors: Ma Yingyu , Yu Wei-Dong , Hershberger Pamela A. , Flynn Geraldine , Kong Rui-Xian , Trump Donald L. , Johnson Candace S. 
Published: September 2008

Abstract
1α,25-Dihydroxyvitamin D3 (1,25D3) exhibits antitumor activity in a variety of cancers including squamous cell carcinoma (SCC). Intrinsic resistance of SCC cells to cisplatin was observed and led to the investigation into whether 1,25D3 sensitizes SCC cells to cisplatin. Pretreatment with 1,25D3 followed by cisplatin enhanced growth inhibition in SCC cells compared with 1,25D3 alone as assessed by cytotoxicity and in vitro clonogenic assays. In addition, 1,25D3 sensitized SCC cells to cisplatin-mediated apoptosis. Treatment of tumor-bearing C3H mice with 1,25D3 before cisplatin reduced clonogenic survival using in vivo excision clonogenic assay. These results were not observed in a 1,25D3-resistant SCC variant, indicating the critical role of 1,25D3 in sensitizing SCC cells to cisplatin. Further, a marked decrease in fractional tumor volume was observed when SCC tumor-bearing mice were treated with 1,25D3 before cisplatin compared with either agent administered alone. Cisplatin has been shown to modulate p73 protein level in certain cancer cells. Our data showed that p73 level was not affected by cisplatin but increased by 1,25D3 in SCC cells. Knocking down p73 by small interfering RNA protected SCC cells against 1,25D3 and cisplatin-mediated clonogenic cell kill and apoptosis. Increasing p73 protein level by knocking down UFD2a, which mediates p73 degradation, promoted 1,25D3 and cisplatin-mediated clonogenic cell kill. These results suggest that 1,25D3 potentiates cisplatin antitumor activity in vitro and in vivo in a SCC model system possibly through p73 induction and apoptosis. The combination treatment may provide a more effective therapeutic regimen in cancer treatment. [Mol Cancer Ther 2008;7(9):3047–55]
Metastasis is strongly reduced by the matrix metalloproteinase inhibitor Galardin in the MMTV-PymT transgenic breast cancer model
Authors: Almholt Kasper , Juncker-Jensen Anna , Lærum Ole Didrik , Danø Keld , Johnsen Morten , Lund Leif Røge , Rømer John 
Published: September 2008

Abstract
Matrix metalloproteinases (MMP) have several roles that influence cancer progression and dissemination. However, low molecular weight metalloproteinase inhibitors (MPI) have not yet been tested in transgenic/spontaneous metastasis models. We have tested Galardin/GM6001, a potent MPI that reacts with most MMPs, in the MMTV-PymT transgenic breast cancer model. We followed a cohort of 81 MMTV-PymT transgenic mice that received Galardin, placebo, or no treatment. Galardin treatment was started at age 6 weeks with 100 mg/kg/d, and all mice were killed at age 13.5 weeks. Galardin treatment significantly reduced primary tumor growth. Final tumor burden in Galardin-treated mice was 1.69 cm3 compared with 3.29 cm3 in placebo-treated mice (t test, P = 0.0014). We quantified the total lung metastasis volume in the same cohort of mice. The median metastasis volume was 0.003 mm3 in Galardin-treated mice compared with 0.56 mm3 in placebo-treated mice (t test, P &lt; 0.0001). Thus, metastasis burden was reduced more than 100-fold, whereas primary tumor size was reduced only 2-fold. We also found that primary tumors from Galardin-treated mice exhibited a lower histopathologic tumor grade, increased collagen deposition, and increased MMP-2 activity. MMPs are known to have tumor-promoting and tumor-inhibitory effects, and several clinical trials of broad-spectrum MPIs have failed to show promising effects. The very potent antimetastatic effect of Galardin in the MMTV-PymT model does, however, show that it may be possible to find broad-spectrum MPIs with favorable inhibition profiles, or perhaps combinations of monospecific MPIs, for future clinical application. [Mol Cancer Ther 2008;7(9):2758–67]
Early drug development of inhibitors of the insulin-like growth factor-I receptor pathway: Lessons from the first clinical trials
Authors: Rodon Jordi , DeSantos Victoria , Ferry Robert Jean , Kurzrock Razelle 
Published: September 2008

Abstract
The insulin-like growth factor-I receptor (IGF-IR) was first cloned in 1986. Since then, intense work has defined classic phosphorelays activated via the IGF-IR, which regulate cell proliferation, apoptosis, motility, and fate. The understanding of the roles of hormones in cancer and the growth hormone–IGF–IGF-binding protein axis specifically has yield to a second wave of development: the design of specific inhibitors that interrupt the signaling associated with this axis. The ability to manipulate these pathways holds not only significant therapeutic implications but also increase the chance of deeper insight about the role of the axis in carcinogenesis and metastasis. Nowadays, &gt;25 molecules with the same goal are at different stages of development. Here, we review the clinical and preclinical experience with the two most-investigated strategies, tyrosine kinase inhibitors and monoclonal antibodies, and the advantages and disadvantages of each strategy, as well as other alternatives and possible drug combinations. We also review the biomarkers explored in the first clinical trials, the strategies that have been explored thus far, and the clinical trials that are going to explore their role in cancer treatment. [Mol Cancer Ther 2008;7(9):2575–88]
Novel opportunities for thymidylate metabolism as a therapeutic target
Authors: Wilson Peter M. , Fazzone William , LaBonte Melissa J. , Deng Jinxia , Neamati Nouri , Ladner Robert D. 
Published: September 2008

AbstractFor over 40 years, the fluoropyrimidine 5-fluorouracil (5-FU) has remained the central agent in therapeutic regimens employed in the treatment of colorectal cancer and is frequently combined with the DNA-damaging agents oxaliplatin and irinotecan, increasing response rates and improving overall survival. However, many patients will derive little or no benefit from treatment, highlighting the need to identify novel therapeutic targets to improve the efficacy of current 5-FU-based chemotherapeutic strategies. dUTP nucleotidohydrolase (dUTPase) catalyzes the hydrolysis of dUTP to dUMP and PPi, providing substrate for thymidylate synthase (TS) and DNA synthesis and repair. Although dUTP is a normal intermediate in DNA synthesis, its accumulation and misincorporation into DNA as uracil is lethal. Importantly, uracil misincorporation represents an important mechanism of cytotoxicity induced by the TS-targeted class of chemotherapeutic agents including 5-FU. A growing body of evidence suggests that dUTPase is an important mediator of response to TS-targeted agents. In this article, we present further evidence showing that elevated expression of dUTPase can protect breast cancer cells from the expansion of the intracellular uracil pool, translating to reduced growth inhibition following treatment with 5-FU. We therefore report the implementation of in silico drug development techniques to identify and develop small-molecule inhibitors of dUTPase. As 5-FU and the oral 5-FU prodrug capecitabine remain central agents in the treatment of a variety of malignancies, the clinical utility of a small-molecule inhibitor to dUTPase represents a viable strategy to improve the clinical efficacy of these mainstay chemotherapeutic agents. [Mol Cancer Ther 2008;7(9):3029–37]
Purified human chorionic gonadotropin induces apoptosis in breast cancer
Authors: Lopez Dayami , Sekharam Madhavi , Coppola Domenico , Carter W. Bradford 
Published: September 2008

Abstract
Agents that induce apoptosis in breast cancer cells have great potential to facilitate chemotherapeutic intervention and improve patient outcomes. In this study, the effects of injecting purified human chorionic gonadotropin (hCG) directly into human breast cancer xenografts grown in nude mice were examined. It was shown that intratumoral injection of purified hCG increased the apoptotic index in breast cancer xenografts. These results were supported by the findings that exposure of breast cancer cells to purified hCG decreased cell viability in five different breast cancer cell lines. In some of these cell lines, the effects of hCG in cell viability appear to correlate with activation/expression of the hCG/luteinizing hormone receptor. Preoperative apoptotic induction by factors such as purified hCG may improve local control or work synergistically with neoadjuvant chemotherapy to improve complete pathologic response of locally advanced breast cancer. [Mol Cancer Ther 2008;7(9):2837–8]
Molecular chemotherapy of pancreatic cancer using novel mutant bacterial cytosine deaminase gene
Authors: Kaliberova Lyudmila N. , Della Manna Debbie L. , Krendelchtchikova Valentina , Black Margaret E. , Buchsbaum Donald J. , Kaliberov Sergey A. 
Published: September 2008

Abstract
The combination of molecular chemotherapy with radiation therapy has the potential to become a powerful approach for treatment of pancreatic cancer. We have developed an adenoviral vector (AdbCD-D314A) encoding a mutant bacterial cytosine deaminase (bCD) gene, which converts the prodrug 5-fluorocytosine (5-FC) into the active drug 5-fluorouracil. The aim of this study was to investigate AdbCD-D314A/5-FC-mediated cytotoxicity in vitro and therapeutic efficacy in vivo alone and in combination with radiation against human pancreatic cancer cells and xenografts. AdbCD-D314A/5-FC-mediated cytotoxicity alone and in combination with radiation was analyzed using crystal violet inclusion and clonogenic survival assays. CD enzyme activity was determined by measuring conversion of [3H]5-FC to [3H]5-fluorouracil after adenoviral infection of pancreatic cancer cells in vitro and pancreatic tumor xenografts by TLC. S.c. pancreatic tumor xenografts were used to evaluate the therapeutic efficacy of AdbCD-D314A/5-FC molecular chemotherapy in combination with radiation therapy. AdbCD-D314A infection resulted in increased 5-FC-mediated pancreatic cancer cell killing that correlated with significantly enhanced CD enzyme activity compared with AdbCDwt encoding wild-type of bCD. Animal studies showed significant inhibition of growth of human pancreatic tumors treated with AdbCD-D314A/5-FC in comparison with AdbCDwt/5-FC. Also, a significantly greater inhibition of growth of Panc2.03 and MIA PaCA-2 tumor xenografts was produced by the combination of AdbCD-D314A/5-FC with radiation compared with either agent alone. The results indicate that the combination of AdbCD-D314A/5-FC molecular chemotherapy with radiation therapy significantly enhanced cytotoxicity of pancreatic cancer cells in vitro and increased therapeutic efficacy against human pancreatic tumor xenografts. [Mol Cancer Ther 2008;7(9):2845–54]
Mitogen-activated protein kinase kinase 1/2 inhibitors and 17-allylamino-17-demethoxygeldanamycin synergize to kill human gastrointestinal tumor cells in vitro via suppression of c-FLIP-s levels and activation of CD95
Authors: Park Margaret A. , Zhang Guo , Mitchell Clint , Rahmani Mohamed , Hamed Hossein , Hagan Michael P. , Yacoub Adly , Curiel David T. , Fisher Paul B. , Grant Steven , Dent Paul 
Published: September 2008

Abstract
Prior studies have noted that inhibitors of mitogen-activated protein kinase (MAPK) kinase 1/2 (MEK1/2) enhanced geldanamycin lethality in malignant hematopoietic cells by promoting mitochondrial dysfunction. The present studies focused on defining the mechanism(s) by which these agents altered survival in carcinoma cells. MEK1/2 inhibitors [PD184352; AZD6244 (ARRY-142886)] interacted in a synergistic manner with geldanamycins [17-allylamino-17-demethoxygeldanamycin (17AAG) and 17-dimethylaminoethylamino-17-demethoxy-geldanamycin] to kill hepatoma and pancreatic carcinoma cells that correlated with inactivation of extracellular signal-regulated kinase 1/2 and AKT and with activation of p38 MAPK; p38 MAPK activation was reactive oxygen species dependent. Treatment of cells with MEK1/2 inhibitors and 17AAG reduced expression of c-FLIP-s that was mechanistically connected to loss of MEK1/2 and AKT function; inhibition of caspase-8 or overexpression of c-FLIP-s abolished cell killing by MEK1/2 inhibitors and 17AAG. Treatment of cells with MEK1/2 inhibitors and 17AAG caused a p38 MAPK-dependent plasma membrane clustering of CD95 without altering the levels or cleavage of FAS ligand. In parallel, treatment of cells with MEK1/2 inhibitors and 17AAG caused a p38 MAPK-dependent association of caspase-8 with CD95. Inhibition of p38 MAPK or knockdown of BID, FAS-associated death domain, or CD95 expression suppressed MEK1/2 inhibitor and 17AAG lethality. Similar correlative data were obtained using a xenograft flank tumor model system. Our data show that treatment of tumor cells with MEK1/2 inhibitors and 17AAG induces activation of the extrinsic pathway and that suppression of c-FLIP-s expression is crucial in transduction of the apoptotic signal from CD95 to promote cell death. [Mol Cancer Ther 2008;7(9):2633–48]
Mithramycin SK modulates polyploidy and cell death in colon carcinoma cells
Authors: Bataller Marc , Méndez Carmen , Salas José A. , Portugal José 
Published: September 2008

Abstract
During a normal cell cycle, polyploidy and aneuploidy can be prevented by several checkpoints, which are mainly p53 dependent. Here, we show that treatment of HCT-116 (p53+/+) colon carcinoma cells with the novel antitumor antibiotic mithramycin SK (MSK) results in polyploidization and mitotic catastrophe, which occurs after a transient halt in G1 phase followed by the overtaking of the G2-M checkpoint when treated cells are incubated in a fresh drug-free medium. Cells reentering aberrant mitosis mainly died by necrosis, although active caspase-3 was observed. Our results indicate that a decrease in p53 RNA and protein levels, together with concomitant changes in the expression of other proteins such as p21WAF1, were involved in MSK-induced polyploidy. Furthermore, the effects of MSK on HCT-116 (p53+/+) cells cannot be attributed exclusively to the down-regulation of p53 by MSK, because these effects differed from those observed in MSK-treated HCT-116 (p53−/−) cells. The p53−/− cells died mainly from G2-M through early p53-independent apoptosis, which appeared to be mediated by caspase-2, although secondary necrosis was also observed. [Mol Cancer Ther 2008;7(9):2988–97]
A role for macroautophagy in protection against 4-hydroxytamoxifen–induced cell death and the development of antiestrogen resistance
Authors: Samaddar Julia S. , Gaddy Virgil T. , Duplantier Jennifer , Thandavan Sudharsan Periyasamy , Shah Manish , Smith Marlena J. , Browning Darren , Rawson Jim , Smith Sylvia B. , Barrett John T. , Schoenlein Patricia V. 
Published: September 2008

Abstract
This study identifies macroautophagy as a key mechanism of cell survival in estrogen receptor–positive (ER+) breast cancer cells undergoing treatment with 4-hydroxytamoxifen (4-OHT). This selective ER modifier is an active metabolite of tamoxifen commonly used for the treatment of breast cancer. Our study provides the following key findings: (a) only 20% to 25% of breast cancer cells treated with 4-OHT in vitro die via caspase-dependent cell death; more typically, the antiestrogen-treated ER+ breast cancer cells express increased levels of macroautophagy and are viable; (b) 4-OHT–induced cell death, but not 4-OHT–induced macroautophagy, can be blocked by the pan-caspase inhibitor z-VAD-fmk, providing strong evidence that these two outcomes of antiestrogen treatment are not linked in an obligatory manner; (c) 4-OHT–resistant cells selected from ER+ breast cancer cells show an increased ability to undergo antiestrogen-induced macroautophagy without induction of caspase-dependent cell death; and (d) 4-OHT, when used in combination with inhibitors of autophagosome function, induces robust, caspase-dependent apoptosis of ER+, 4-OHT–resistant breast cancer cells. To our knowledge, these studies provide the first evidence that macroautophagy plays a critical role in the development of antiestrogen resistance. We propose that targeting autophagosome function will improve the efficacy of hormonal treatment of ER+ breast cancer. [Mol Cancer Ther 2008;7(9):2977–87]
Keratin down-regulation in vimentin-positive cancer cells is reversible by vimentin RNA interference, which inhibits growth and motility
Authors: Paccione Rachel J. , Miyazaki Hiroshi , Patel Vyomesh , Waseem Ahmad , Gutkind J. Silvio , Zehner Zendra E. , Yeudall W. Andrew 
Published: September 2008

Abstract
At later stages of tumor progression, epithelial carcinogenesis is associated with transition to a mesenchymal phenotype, which may contribute to the more aggressive properties of cancer cells and may be stimulated by growth factors such as epidermal growth factor and transforming growth factor-β. Previously, we found that cells derived from a nodal metastatic squamous cell carcinoma are highly proliferative and motile in vitro and tumorigenic in vivo. In the current study, we have investigated the role of vimentin in proliferation and motility. Cells derived from nodal metastasis express high levels of vimentin, which is undetectable in tumor cells derived from a synchronous primary lesion of tongue. Vimentin expression was enhanced by epidermal growth factor and transforming growth factor-β both independently and in combination. Use of RNA interference resulted in the generation of stable cell lines that express constitutively low levels of vimentin. RNA interference-mediated vimentin knockdown reduced cellular proliferation, migration, and invasion through a basement membrane substitute by 3-fold compared with nontargeting controls. In addition, cells with reduced vimentin reexpressed differentiation-specific keratins K13, K14, and K15 as a result of increased gene transcription as judged by quantitative PCR and promoter-reporter assays. Furthermore, cells in which vimentin expression was reduced showed a greatly decreased tumorigenic potential, as tumors developing from these cells were 70% smaller than those from control cells. The data suggest that reversal of the mesenchymal phenotype by inhibiting vimentin expression results in reexpression of epithelial characteristics and reduced tumor aggressiveness. [Mol Cancer Ther 2008;7(9):2894–903]