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Source: Molecular Cancer Research
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Total 53 results found since Jan 2013.
Chemoradiotherapy Resistance in Colorectal Cancer Cells is Mediated by Wnt/{beta}-catenin Signaling
Activation of Wnt/β-catenin signaling plays a central role in the development and progression of colorectal cancer. The Wnt-transcription factor, TCF7L2, is overexpressed in primary rectal cancers that are resistant to chemoradiotherapy and TCF7L2 mediates resistance to chemoradiotherapy. However, it is unclear whether the resistance is mediated by a TCF7L2 inherent mechanism or Wnt/β-catenin signaling in general. Here, inhibition of β-catenin by siRNAs or a small-molecule inhibitor (XAV-939) resulted in sensitization of colorectal cancer cells to chemoradiotherapy. To investigate the potential role of Wnt/&...
Source: Molecular Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Emons, G., Spitzner, M., Reineke, S., Möller, J., Auslander, N., Kramer, F., Hu, Y., Beissbarth, T., Wolff, H. A., Rave-Fränk, M., Hessmann, E., Gaedcke, J., Ghadimi, B. M., Johnsen, S. A., Ried, T., Grade, M. Tags: Cell Death and Survival Source Type: research
NR4A2 Promotes DNA Double-strand Break Repair Upon Exposure to UVR
Exposure of melanocytes to ultraviolet radiation (UVR) induces the formation of UV lesions that can produce deleterious effects in genomic DNA. Encounters of replication forks with unrepaired UV lesions can lead to several complex phenomena, such as the formation of DNA double-strand breaks (DSBs). The NR4A family of nuclear receptors are transcription factors that have been associated with mediating DNA repair functions downstream of the MC1R signaling pathway in melanocytes. In particular, emerging evidence shows that upon DNA damage, the NR4A2 receptor can translocate to sites of UV lesion by mechanisms requiring post-t...
Source: Molecular Cancer Research - August 31, 2017 Category: Cancer & Oncology Authors: Yin, K., Chhabra, Y., Tropee, R., Lim, Y. C., Fane, M., Dray, E., Sturm, R. A., Smith, A. G. Tags: DNA Damage and Repair Source Type: research
Therapeutic Targeting of PTK7 is Cytotoxic in Atypical Teratoid Rhabdoid Tumors
Novel discoveries involving the evaluation of potential therapeutics are based on newly identified molecular targets for atypical teratoid rhabdoid tumors (ATRT), which are the most common form of infantile brain tumors. Central nervous system ATRTs are rare, aggressive, and fast growing tumors of the brain and spinal cord and carry a very poor prognosis. Currently, the standard of care for ATRT patients is based on surgical resection followed by systemic chemotherapy and radiotherapy, which result in severe side effects. As protein tyrosine kinases have proven to be actionable targets that reduce tumor growth in a number ...
Source: Molecular Cancer Research - August 1, 2017 Category: Cancer & Oncology Authors: Messerli, S. M., Hoffman, M. M., Gnimpieba, E. Z., Bhardwaj, R. D. Tags: Cell Death and Survival Source Type: research
Differential Expression of OATP1B3 Mediates Unconjugated Testosterone Influx
This study was undertaken to ascertain the androgen uptake kinetics, functional, and clinical relevance of de novo expression of the steroid hormone transporter OATP1B3 (SLCO1B3). Experiments testing the cellular uptake of androgens suggest that testosterone is an excellent substrate of OATP1B3 (Km = 23.2 μmol/L; Vmax = 321.6 pmol/mg/minute), and cells expressing a doxycycline-inducible SLCO1B3 construct had greater uptake of a clinically relevant concentration of 3H-testosterone (50 nmol/L; 1.6-fold, P = 0.0027). When compared with Slco1b2 (–/–) mice, Slco1b2 (–/–)/hSLCO1B3 knockins had greater ...
Source: Molecular Cancer Research - August 1, 2017 Category: Cancer & Oncology Authors: Sissung, T. M., Ley, A. M., Strope, J. D., McCrea, E. M., Beedie, S., Peer, C. J., Shukla, S., van Velkinburgh, J., Reece, K., Troutman, S., Campbell, T., Fernandez, E., Huang, P., Smith, J., Thakkar, N., Venzon, D. J., Brenner, S., Lee, W., Merino, M., L Tags: Signal Transduction Source Type: research
Constitutive Phosphorylation of STAT3 by the CK2-BLNK-CD5 Complex
In chronic lymphocytic leukemia (CLL), STAT3 is constitutively phosphorylated on serine 727 and plays a role in the pathobiology of CLL. However, what induces constitutive phosphorylation of STAT3 is currently unknown. Mass spectrometry was used to identify casein kinase 2 (CK2), a serine/threonine kinase that coimmunoprecipitated with serine phosphorylated STAT3 (pSTAT3). Furthermore, activated CK2 incubated with recombinant STAT3 induced phosphorylation of STAT3 on serine 727. Although STAT3 and CK2 are present in normal B- and T cells, STAT3 is not constitutively phosphorylated in these cells. Further study found that C...
Source: Molecular Cancer Research - May 1, 2017 Category: Cancer & Oncology Authors: Rozovski, U., Harris, D. M., Li, P., Liu, Z., Jain, P., Veletic, I., Ferrajoli, A., Burger, J., O'Brien, S., Bose, P., Thompson, P., Jain, N., Wierda, W., Keating, M. J., Estrov, Z. Tags: Signal Transduction Source Type: research
Abstract B21: The selective ATR inhibitor VX-970 enhances the therapeutic effects of standards of care in glioblastoma
Glioblastoma (GBM) represents one of the most aggressive cancer types with the vast majority of patients succumbing to disease within the first five years. This dire prognosis reflects the limited efficacy of our frontline therapies which include radiation therapy and temozolomide (TMZ) chemotherapy. The cellular response to these therapies is critically mediated by DNA damage response signaling networks that are regulated by Ataxia Telangiectasia Mutated (ATM) and Ataxia Telangiectasia And Rad3-Related Protein (ATR). Preliminary studies from our laboratory suggest the ATR inhibitor VX-970 has single agent efficacy in both...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Burgenske, D., Mladek, A., Sarkaria, J. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Poster Presentations - Proffered Abstracts Source Type: research
Abstract B45: A genome-scale screen identifies the microcephaly gene, ZNF335, as a regulator of DNA end resection
We examined the recruitment of known resection factors to DSB sites and determined that the localization of CtIP and BLM were impaired in cells depleted of ZNF335. Our data suggests that ZNF335 plays an important role in promoting resection and ATR activation in response to DSBs.Citation Format: Jordan Young, Mikhail Bashkurov, Andrea McEwan, Thomas Sun, Alessandro Datti, Daniel Durocher. A genome-scale screen identifies the microcephaly gene, ZNF335, as a regulator of DNA end resection [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montre...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Young, J., Bashkurov, M., McEwan, A., Sun, T., Datti, A., Durocher, D. Tags: Exploiting Repair Defects in the Tumor Microenvironment: Poster Presentations - Proffered Abstracts Source Type: research
Autophagy Inhibition Enhances Sunitinib Efficacy in Clear Cell Ovarian Carcinoma
This study shows that autophagy inhibition enhances sunitinib-mediated cell death in a preclinical model of CCOC. Mol Cancer Res; 15(3); 250–8. ©2017 AACR.
Source: Molecular Cancer Research - February 27, 2017 Category: Cancer & Oncology Authors: DeVorkin, L., Hattersley, M., Kim, P., Ries, J., Spowart, J., Anglesio, M. S., Levi, S. M., Huntsman, D. G., Amaravadi, R. K., Winkler, J. D., Tinker, A. V., Lum, J. J. Tags: Cell Death and Survival Source Type: research
ERK/MAPK Signaling Drives Overexpression of the Rac-GEF, PREX1, in BRAF- and NRAS-Mutant Melanoma
This study identifies an ERK-dependent mechanism that drives PREX1 upregulation and subsequent RAC1-dependent invasion in BRAF- and NRAS-mutant melanoma. Mol Cancer Res; 14(10); 1009–18. ©2016 AACR.
Source: Molecular Cancer Research - October 12, 2016 Category: Cancer & Oncology Authors: Ryan, M. B., Finn, A. J., Pedone, K. H., Thomas, N. E., Der, C. J., Cox, A. D. Tags: Signal Transduction Source Type: research
ERK Regulates PREX1-RAC1 in Human Melanoma
This study identifies an ERK-dependent mechanism that drives PREX1 upregulation and subsequent RAC1-dependent invasion in BRAF- and NRAS-mutant melanoma. Mol Cancer Res; 14(10); 1009–18. ©2016 AACR.
Source: Molecular Cancer Research - October 12, 2016 Category: Cancer & Oncology Authors: Ryan, M. B., Finn, A. J., Pedone, K. H., Thomas, N. E., Der, C. J., Cox, A. D. Tags: Signal Transduction Source Type: research
HuR Mediates TRAIL Resistance
Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal cancers, in part, due to resistance to both conventional and targeted therapeutics. TRAIL directly induces apoptosis through engagement of cell surface Death Receptors (DR4 and DR5), and has been explored as a molecular target for cancer treatment. Clinical trials with recombinant TRAIL and DR-targeting agents, however, have failed to show overall positive outcomes. Herein, we identify a novel TRAIL resistance mechanism governed by Hu antigen R (HuR, ELAV1), a stress-response protein abundant and functional in PDA cells. Exogenous HuR overexpression in TRAIL-...
Source: Molecular Cancer Research - July 16, 2016 Category: Cancer & Oncology Authors: Romeo, C., Weber, M. C., Zarei, M., DeCicco, D., Chand, S. N., Lobo, A. D., Winter, J. M., Sawicki, J. A., Sachs, J. N., Meisner-Kober, N., Yeo, C. J., Vadigepalli, R., Tykocinski, M. L., Brody, J. R. Tags: Cell Death and Survival Source Type: research
Abstract B29: Snail regulates extracellular matrix-mediated VEGFR3 expression in developmental and tumor angiogenesis
Snail family is a zinc finger transcription factor and involved in epithelial branching morphogenesis and EMT by altering the ability of polarity, motility, and adhesion. The expression of Snail family in developing and tumor vessels has been suggested, however, the precise expression pattern and cellular function of Snail remain to be unclear. We identified Snail as an angiogenic regulator through inducing VEGFR3 under extracellular matrix (ECM)-meditated signalings. Snail was upregulated in the postnatally developing retinal endothelial cells (ECs) and in the vessels lining ductal breast tumors. In vitro endothelial spro...
Source: Molecular Cancer Research - May 2, 2016 Category: Cancer & Oncology Authors: Park, J. A., Lee, H.-Y., Kwon, Y.-G. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research
miR-155 Overexpression Promotes Genomic Instability
miR-155 is an oncogenic miRNA that is often overexpressed in cancer and is associated with poor prognosis. miR-155 can target several DNA repair factors, including RAD51, MLH1, and MSH6, and its overexpression results in an increased mutation frequency in vitro, although the mechanism has yet to be fully understood. Here, we demonstrate that overexpression of miR-155 drives an increased mutation frequency both in vitro and in vivo, promoting genomic instability by affecting multiple DNA repair pathways. miR-155 overexpression causes a decrease in homologous recombination, but yields a concurrent increase in the error-prone...
Source: Molecular Cancer Research - April 13, 2016 Category: Cancer & Oncology Authors: Czochor, J. R., Sulkowski, P., Glazer, P. M. Tags: DNA Damage and Repair Source Type: research
Abstract IA06: Spatial systems biology of cancer
International efforts have now defined the genomic landscapes of most major human cancer types. The genomic landscape of breast cancer is particularly well described in several recent publications. The high level view of this disease suggests a remarkable level of inter- and intra-tumor heterogeneity, the presence of a few recurrent and many rare genomic aberrations and substantial genomic and epigenomic heterogeneity. The challenge now is to understand how these aberrations and tumor extrinsic influences from the microenvironment collaborate to deregulate aspects of cell differentiation, proliferation, apoptosis, DNA repa...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Gray, J. Tags: Genomics - Sporadic and Hereditary: Oral Presentations - Invited Abstracts Source Type: research
Abstract PR06: Modeling the tumor microenvironment to identify novel loss of function mutations in breast cancer progression
Recent next generation sequencing studies have comprehensively mapped the genetic landscape of breast cancer and revealed that only a small number of genes are recurrently mutated in more than 10% of unselected tumors (i.e. TP53, PIK3CA and GATA3), and that the vast majority of recurrent mutations occur at low frequencies. Although some have been shown to be drivers (i.e. confer a selective advantage), such as oncogenic ERBB2 mutations, there is a myriad of significantly altered lower frequency mutations whose functional impact is unknown.We utilized a functional genomics approach silencing the 200 most frequently mutated ...
Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Peck, B., Maguire, S., Morrison, E., Wai, P., Natrajan, R. Tags: Tumor Heterogeneity (Intratumor and Intertumoral): Oral Presentations - Proffered Abstracts Source Type: research
