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Helicobacter pylori pathogen regulates p14ARF tumor suppressor and autophagy in gastric epithelial cells.
Horvat A, Noto JM, Ramatchandirin B, Zaika E, Palrasu M, Wei J, Schneider BG, El-Rifai W, Peek RM, Zaika AI
(2018) Oncogene 37: 5054-5065
MeSH Terms: Antigens, Bacterial, Autophagy, Bacterial Proteins, Cell Line, Tumor, Down-Regulation, Epithelial Cells, Gastric Mucosa, HCT116 Cells, Helicobacter Infections, Helicobacter pylori, Humans, Signal Transduction, Stomach, Stomach Neoplasms, Tumor Suppressor Protein p14ARF, Tumor Suppressor Protein p53, Ubiquitin-Protein Ligases, Up-Regulation, Virulence Factors
Show Abstract · Added September 25, 2018
Infection with Helicobacter pylori is one of the strongest risk factors for development of gastric cancer. Although these bacteria infect approximately half of the world's population, only a small fraction of infected individuals develops gastric malignancies. Interactions between host and bacterial virulence factors are complex and interrelated, making it difficult to elucidate specific processes associated with H. pylori-induced tumorigenesis. In this study, we found that H. pylori inhibits p14ARF tumor suppressor by inducing its degradation. This effect was found to be strain-specific. Downregulation of p14ARF induced by H. pylori leads to inhibition of autophagy in a p53-independent manner in infected cells. We identified TRIP12 protein as E3 ubiquitin ligase that is upregulated by H. pylori, inducing ubiquitination and subsequent degradation of p14ARF protein. Using isogenic H. pylori mutants, we found that induction of TRIP12 is mediated by bacterial virulence factor CagA. Increased expression of TRIP12 protein was found in infected gastric epithelial cells in vitro and human gastric mucosa of H. pylori-infected individuals. In conclusion, our data demonstrate a new mechanism of ARF inhibition that may affect host-bacteria interactions and facilitate tumorigenic transformation in the stomach.
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19 MeSH Terms
Pharmacological blockade of ASCT2-dependent glutamine transport leads to antitumor efficacy in preclinical models.
Schulte ML, Fu A, Zhao P, Li J, Geng L, Smith ST, Kondo J, Coffey RJ, Johnson MO, Rathmell JC, Sharick JT, Skala MC, Smith JA, Berlin J, Washington MK, Nickels ML, Manning HC
(2018) Nat Med 24: 194-202
MeSH Terms: Amino Acid Transport System ASC, Animals, Cell Line, Tumor, Cell Proliferation, Computer Simulation, Disease Models, Animal, Glutamine, HCT116 Cells, Humans, Mice, Minor Histocompatibility Antigens, Neoplasms, Oxidative Stress, Signal Transduction, Small Molecule Libraries
Show Abstract · Added March 14, 2018
The unique metabolic demands of cancer cells underscore potentially fruitful opportunities for drug discovery in the era of precision medicine. However, therapeutic targeting of cancer metabolism has led to surprisingly few new drugs to date. The neutral amino acid glutamine serves as a key intermediate in numerous metabolic processes leveraged by cancer cells, including biosynthesis, cell signaling, and oxidative protection. Herein we report the preclinical development of V-9302, a competitive small molecule antagonist of transmembrane glutamine flux that selectively and potently targets the amino acid transporter ASCT2. Pharmacological blockade of ASCT2 with V-9302 resulted in attenuated cancer cell growth and proliferation, increased cell death, and increased oxidative stress, which collectively contributed to antitumor responses in vitro and in vivo. This is the first study, to our knowledge, to demonstrate the utility of a pharmacological inhibitor of glutamine transport in oncology, representing a new class of targeted therapy and laying a framework for paradigm-shifting therapies targeting cancer cell metabolism.
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15 MeSH Terms
MDM2 Antagonists Counteract Drug-Induced DNA Damage.
Vilgelm AE, Cobb P, Malikayil K, Flaherty D, Andrew Johnson C, Raman D, Saleh N, Higgins B, Vara BA, Johnston JN, Johnson DB, Kelley MC, Chen SC, Ayers GD, Richmond A
(2017) EBioMedicine 24: 43-55
MeSH Terms: Animals, Antineoplastic Combined Chemotherapy Protocols, Azepines, Cell Line, Tumor, Cyclin-Dependent Kinase Inhibitor p21, DNA Damage, DNA Replication, HCT116 Cells, Humans, Imidazoles, Melanoma, Mice, Piperazines, Protein Binding, Proto-Oncogene Proteins c-mdm2, Pyrimidines, Pyrrolidines, Tumor Suppressor Protein p53, Xenograft Model Antitumor Assays, para-Aminobenzoates
Show Abstract · Added June 20, 2018
Antagonists of MDM2-p53 interaction are emerging anti-cancer drugs utilized in clinical trials for malignancies that rarely mutate p53, including melanoma. We discovered that MDM2-p53 antagonists protect DNA from drug-induced damage in melanoma cells and patient-derived xenografts. Among the tested DNA damaging drugs were various inhibitors of Aurora and Polo-like mitotic kinases, as well as traditional chemotherapy. Mitotic kinase inhibition causes mitotic slippage, DNA re-replication, and polyploidy. Here we show that re-replication of the polyploid genome generates replicative stress which leads to DNA damage. MDM2-p53 antagonists relieve replicative stress via the p53-dependent activation of p21 which inhibits DNA replication. Loss of p21 promoted drug-induced DNA damage in melanoma cells and enhanced anti-tumor activity of therapy combining MDM2 antagonist with mitotic kinase inhibitor in mice. In summary, MDM2 antagonists may reduce DNA damaging effects of anti-cancer drugs if they are administered together, while targeting p21 can improve the efficacy of such combinations.
Copyright © 2017. Published by Elsevier B.V.
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MeSH Terms
Differential abundance of CK1α provides selectivity for pharmacological CK1α activators to target WNT-dependent tumors.
Li B, Orton D, Neitzel LR, Astudillo L, Shen C, Long J, Chen X, Kirkbride KC, Doundoulakis T, Guerra ML, Zaias J, Fei DL, Rodriguez-Blanco J, Thorne C, Wang Z, Jin K, Nguyen DM, Sands LR, Marchetti F, Abreu MT, Cobb MH, Capobianco AJ, Lee E, Robbins DJ
(2017) Sci Signal 10:
MeSH Terms: Animals, Antineoplastic Agents, Benzoates, Casein Kinase Ialpha, Enzyme Activation, Enzyme Activators, Gene Expression Regulation, Neoplastic, HCT116 Cells, Humans, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Nude, Neoplasm Metastasis, Neoplasms, Organ Culture Techniques, Phosphorylation, Pyrvinium Compounds, Signal Transduction, Surface Plasmon Resonance, Wnt Proteins, Wnt Signaling Pathway, Xenograft Model Antitumor Assays, Xenopus laevis
Show Abstract · Added July 18, 2017
Constitutive WNT activity drives the growth of various human tumors, including nearly all colorectal cancers (CRCs). Despite this prominence in cancer, no WNT inhibitor is currently approved for use in the clinic largely due to the small number of druggable signaling components in the WNT pathway and the substantial toxicity to normal gastrointestinal tissue. We have shown that pyrvinium, which activates casein kinase 1α (CK1α), is a potent inhibitor of WNT signaling. However, its poor bioavailability limited the ability to test this first-in-class WNT inhibitor in vivo. We characterized a novel small-molecule CK1α activator called SSTC3, which has better pharmacokinetic properties than pyrvinium, and found that it inhibited the growth of CRC xenografts in mice. SSTC3 also attenuated the growth of a patient-derived metastatic CRC xenograft, for which few therapies exist. SSTC3 exhibited minimal gastrointestinal toxicity compared to other classes of WNT inhibitors. Consistent with this observation, we showed that the abundance of the SSTC3 target, CK1α, was decreased in WNT-driven tumors relative to normal gastrointestinal tissue, and knocking down CK1α increased cellular sensitivity to SSTC3. Thus, we propose that distinct CK1α abundance provides an enhanced therapeutic index for pharmacological CK1α activators to target WNT-driven tumors.
Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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24 MeSH Terms
Design, Synthesis, and Biological Activity of Substrate Competitive SMYD2 Inhibitors.
Cowen SD, Russell D, Dakin LA, Chen H, Larsen NA, Godin R, Throner S, Zheng X, Molina A, Wu J, Cheung T, Howard T, Garcia-Arenas R, Keen N, Pendleton CS, Pietenpol JA, Ferguson AD
(2016) J Med Chem 59: 11079-11097
MeSH Terms: Cell Line, Tumor, Cell Proliferation, Dose-Response Relationship, Drug, Drug Design, Enzyme Inhibitors, HCT116 Cells, Histone-Lysine N-Methyltransferase, Humans, Molecular Structure, Structure-Activity Relationship
Show Abstract · Added April 9, 2017
Protein lysine methyltransferases (KMTs) have emerged as important regulators of epigenetic signaling. These enzymes catalyze the transfer of donor methyl groups from the cofactor S-adenosylmethionine to specific acceptor lysine residues on histones, leading to changes in chromatin structure and transcriptional regulation. These enzymes also methylate an array of nonhistone proteins, suggesting additional mechanisms by which they influence cellular physiology. SMYD2 is reported to be an oncogenic methyltransferase that represses the functional activity of the tumor suppressor proteins p53 and RB. HTS screening led to identification of five distinct substrate-competitive chemical series. Determination of liganded crystal structures of SMYD2 contributed significantly to "hit-to-lead" design efforts, culminating in the creation of potent and selective inhibitors that were used to understand the functional consequences of SMYD2 inhibition. Taken together, these results have broad implications for inhibitor design against KMTs and clearly demonstrate the potential for developing novel therapies against these enzymes.
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10 MeSH Terms
A Synthetic Lethal Screen Identifies DNA Repair Pathways that Sensitize Cancer Cells to Combined ATR Inhibition and Cisplatin Treatments.
Mohni KN, Thompson PS, Luzwick JW, Glick GG, Pendleton CS, Lehmann BD, Pietenpol JA, Cortez D
(2015) PLoS One 10: e0125482
MeSH Terms: Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Ataxia Telangiectasia Mutated Proteins, Cell Line, Tumor, Cell Survival, Cisplatin, DNA Repair, DNA-Directed DNA Polymerase, Drug Resistance, Neoplasm, Drug Synergism, Gene Library, HCT116 Cells, Humans, Intracellular Signaling Peptides and Proteins, Pyrazines, RNA, Small Interfering, Sulfones, Tumor Suppressor p53-Binding Protein 1
Show Abstract · Added February 4, 2016
The DNA damage response kinase ATR may be a useful cancer therapeutic target. ATR inhibition synergizes with loss of ERCC1, ATM, XRCC1 and DNA damaging chemotherapy agents. Clinical trials have begun using ATR inhibitors in combination with cisplatin. Here we report the first synthetic lethality screen with a combination treatment of an ATR inhibitor (ATRi) and cisplatin. Combination treatment with ATRi/cisplatin is synthetically lethal with loss of the TLS polymerase ζ and 53BP1. Other DNA repair pathways including homologous recombination and mismatch repair do not exhibit synthetic lethal interactions with ATRi/cisplatin, even though loss of some of these repair pathways sensitizes cells to cisplatin as a single-agent. We also report that ATRi strongly synergizes with PARP inhibition, even in homologous recombination-proficient backgrounds. Lastly, ATR inhibitors were able to resensitize cisplatin-resistant cell lines to cisplatin. These data provide a comprehensive analysis of DNA repair pathways that exhibit synthetic lethality with ATR inhibitors when combined with cisplatin chemotherapy, and will help guide patient selection strategies as ATR inhibitors progress into the cancer clinic.
1 Communities
2 Members
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18 MeSH Terms
Loss of caspase-3 sensitizes colon cancer cells to genotoxic stress via RIP1-dependent necrosis.
Brown MF, Leibowitz BJ, Chen D, He K, Zou F, Sobol RW, Beer-Stolz D, Zhang L, Yu J
(2015) Cell Death Dis 6: e1729
MeSH Terms: Caspase 3, Cell Death, Colonic Neoplasms, DNA Damage, HCT116 Cells, HEK293 Cells, HT29 Cells, Humans, Nuclear Pore Complex Proteins, RNA-Binding Proteins, Transfection
Show Abstract · Added July 28, 2015
Caspase-3 is the best known executioner caspase in apoptosis. We generated caspase-3 knockout (C3KO) and knockdown human colorectal cancer cells, and found that they are unexpectedly sensitized to DNA-damaging agents including 5-fluorouracil (5-FU), etoposide, and camptothecin. C3KO xenograft tumors also displayed enhanced therapeutic response and cell death to 5-FU. C3KO cells showed intact apoptosis and activation of caspase-7 and -9, impaired processing of caspase-8, and induction of necrosis in response to DNA-damaging agents. This form of necrosis is associated with HMGB1 release and ROS production, and suppressed by genetic or pharmacological inhibition of RIP1, MLKL1, or caspase-8, but not inhibitors of pan-caspases or RIP3. 5-FU treatment led to the formation of a z-VAD-resistant pro-caspase-8/RIP1/FADD complex, which was strongly stabilized by caspase-3 KO. These data demonstrate a key role of caspase-3 in caspase-8 processing and suppression of DNA damage-induced necrosis, and provide a potentially novel way to chemosensitize cancer cells.
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11 MeSH Terms
High-yielding, automated production of 3'-deoxy-3'-[(18)F]fluorothymidine using a modified Bioscan Coincidence FDG reaction module.
Cheung YY, Nickels ML, McKinley ET, Buck JR, Manning HC
(2015) Appl Radiat Isot 97: 47-51
MeSH Terms: Animals, Colorectal Neoplasms, Dideoxynucleosides, HCT116 Cells, Heterografts, Humans, Mice, Mice, Nude, Positron-Emission Tomography, Quality Control, Radiochemistry, Radiopharmaceuticals
Show Abstract · Added January 23, 2015
INTRODUCTION - High-yielding, automated production of a PET tracer that reflects proliferation, 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT), is reported using a modified Bioscan Coincidence FDG reaction module.
METHODS - Production of [(18)F]FLT was implemented through: (1) modification of an original FDG manifold; (2) application of an alternate time sequence; and (3) altered solid-phase extraction (SPE) purification. Quality control testing, including standard radiochemical figures of merit and preclinical positron emission tomography (PET) imaging, was carried out.
RESULTS - High decay-corrected yields of [(18)F]FLT (16-39%) were reproducibly obtained. The product exhibited very high specific activity (4586.9TBq/mmol; 123,969Ci/mmol) and radiochemical purity (>99%). Overall, the [(18)F]FLT produced in this manner was superior to typical productions that utilized a GE TRACERlab FXF-N reaction module. Additionally, purification with SPE cartridges, followed by manual elution, accelerated overall run time and resulted in a two-fold increase in [(18)F]FLT concentration. PET imaging showed the [(18)F]FLT produced by this method was highly suitable for non-invasive tumor imaging in mice.
CONCLUSIONS - The Bioscan Coincidence GE FDG Reaction Module was readily adapted to reproducibly provide [(18)F]FLT in high yield, specific activity, and radiochemical purity. The approach was suitable to provide sufficient amounts of material for preclinical studies.
Copyright © 2014 Elsevier Ltd. All rights reserved.
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12 MeSH Terms
Nuclear factor of activated T-cell activity is associated with metastatic capacity in colon cancer.
Tripathi MK, Deane NG, Zhu J, An H, Mima S, Wang X, Padmanabhan S, Shi Z, Prodduturi N, Ciombor KK, Chen X, Washington MK, Zhang B, Beauchamp RD
(2014) Cancer Res 74: 6947-57
MeSH Terms: Animals, Cell Line, Tumor, Colonic Neoplasms, Gene Expression Regulation, Neoplastic, HCT116 Cells, HT29 Cells, Humans, Mice, NFATC Transcription Factors, Neoplasm Invasiveness, Neoplasm Metastasis, Transcription Factors
Show Abstract · Added January 26, 2015
Metastatic recurrence is the leading cause of cancer-related deaths in patients with colorectal carcinoma. To capture the molecular underpinnings for metastasis and tumor progression, we performed integrative network analysis on 11 independent human colorectal cancer gene expression datasets and applied expression data from an immunocompetent mouse model of metastasis as an additional filter for this biologic process. In silico analysis of one metastasis-related coexpression module predicted nuclear factor of activated T-cell (NFAT) transcription factors as potential regulators for the module. Cells selected for invasiveness and metastatic capability expressed higher levels of NFATc1 as compared with poorly metastatic and less invasive parental cells. We found that inhibition of NFATc1 in human and mouse colon cancer cells resulted in decreased invasiveness in culture and downregulation of metastasis-related network genes. Overexpression of NFATc1 significantly increased the metastatic potential of colon cancer cells, whereas inhibition of NFATc1 reduced metastasis growth in an immunocompetent mouse model. Finally, we found that an 8-gene signature comprising genes upregulated by NFATc1 significantly correlated with worse clinical outcomes in stage II and III colorectal cancer patients. Thus, NFATc1 regulates colon cancer cell behavior and its transcriptional targets constitute a novel, biologically anchored gene expression signature for the identification of colon cancers with high risk of metastatic recurrence.
©2014 American Association for Cancer Research.
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12 MeSH Terms
Conjugation of cisplatin analogues and cyclooxygenase inhibitors to overcome cisplatin resistance.
Neumann W, Crews BC, Sárosi MB, Daniel CM, Ghebreselasie K, Scholz MS, Marnett LJ, Hey-Hawkins E
(2015) ChemMedChem 10: 183-92
MeSH Terms: Antineoplastic Agents, Cell Line, Tumor, Cell Proliferation, Cisplatin, Cyclooxygenase 1, Cyclooxygenase 2, Cyclooxygenase Inhibitors, Drug Resistance, Neoplasm, HCT116 Cells, Humans
Show Abstract · Added February 22, 2016
Cyclooxygenase (COX) is an enzyme involved in tumorigenesis and is associated with tumor cell resistance against platinum-based antitumor drugs. Cisplatin analogues were conjugated with COX inhibitors (indomethacin, ibuprofen) to study the synergistic effects that were previously observed in combination treatments. The conjugates ensure concerted transport of both drugs into cells, and subsequent intracellular cleavage enables a dual-action mode. Whereas the platinum(II) complexes showed cytotoxicities similar to those of cisplatin, the platinum(IV) conjugates revealed highly increased cytotoxic activities and were able to completely overcome cisplatin-related resistance. Although some of the complexes are potent COX inhibitors, the conjugates appear to execute their cytotoxic action via COX-independent mechanisms. Instead, the increased lipophilicity and kinetic inertness of the conjugates seem to facilitate cellular accumulation of the platinum drugs and thus improve the efficacy of the antitumor agents. These conjugates are important tools for the elucidation of the direct influence of COX inhibitors on platinum-based anticancer drugs in tumor cells.
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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10 MeSH Terms