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Cancer

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Full-Text Articles in Molecular Biology

Regulation Of The Pi3-Kinase/Pten Signaling Pathway By Tgf-Β In Prostate Cancer Cells, Mawiyah Kimbrough-Allah May 2018

Regulation Of The Pi3-Kinase/Pten Signaling Pathway By Tgf-Β In Prostate Cancer Cells, Mawiyah Kimbrough-Allah

Electronic Theses & Dissertations Collection for Atlanta University & Clark Atlanta University

Transforming growth factor -β (TGF-β) plays an important role in the progression of prostate cancer. It acts as a tumor suppressor in normal epithelial cells but as a tumor promoter in advanced prostate cancer cells. The PI3-kinase pathway has been shown to play integral roles in many cellular processes including cell proliferation, survival, and cell migration in many cell types. PI3-kinase pathway mediates TGF-β effects on prostate cancer cell migration and invasion. Phosphatase and tensin homolog (PTEN), a tumor suppressor gene, inhibits PI3-kinase pathway and is frequently mutated in prostate cancers. In this present study, we investigated possible roles of ...


The Role Of Mafb In Reverting The Transformed Phenotype Of Human Acute Myeloid Leukemia Cells, Tulley Shofner May 2018

The Role Of Mafb In Reverting The Transformed Phenotype Of Human Acute Myeloid Leukemia Cells, Tulley Shofner

Student Honors Theses By Year

The five-year survival rate for patients with acute myeloid leukemia is 27.4%, with most patients who achieve temporary remission relapsing, despite chemotherapeutic treatments (National Cancer Institute, 2014). With the inadequacy of current drug therapies for human acute myeloid leukemia patients, the genetic changes in AML cells’ genomes and transcriptomes have been studied for insights as to more effective targeted therapies. Data obtained by the Roberts lab demonstrates that treatment of HL-60 cells with PMA, which leads to cell cycle arrest, differentiation and apoptosis, is accompanied by upregulation of approximately 100 transcription factor genes. For this project, the basic leucine ...


The Regulation Of Dna Methylation In Mammalian Development And Cancer, Nicolas Veland May 2018

The Regulation Of Dna Methylation In Mammalian Development And Cancer, Nicolas Veland

UT GSBS Dissertations and Theses (Open Access)

DNA methylation is an essential epigenetic modification in mammals, as it plays important regulatory roles in multiple biological processes, such as gene transcription, maintenance of chromosomal structure and genomic stability, genomic imprinting, retrotransposon silencing, and X-chromosome inactivation. Dysregulation of DNA methylation is associated with various human diseases. For example, cancer cells usually show global hypomethylation and regional hypermenthylation, which have been implicated in genomic instability and tumor suppressor silencing, respectively. Although great progress has been made in elucidating the biological functions of DNA methylation over the last several decades, how DNA methylation patterns and levels are regulated and dysregulated is ...


Studies Of Norspermidine Uptake In Drosophila Suggest The Existence Of Multiple Polyamine Transport Pathways, Michael Dieffenbach Jan 2018

Studies Of Norspermidine Uptake In Drosophila Suggest The Existence Of Multiple Polyamine Transport Pathways, Michael Dieffenbach

Honors Undergraduate Theses

Polyamines are a class of essential nutrients involved in many basic cellular processes such as gene expression, cell proliferation, and apoptosis. Without polyamines, cell growth is delayed or halted. Cancerous cells require an abundance of polyamines through a combination of synthesis and transport from the extracellular environment. An FDA-approved drug, D,L-α-difluoromethylornithine (DFMO), blocks polyamine synthesis but is ineffective at inhibiting cell growth due to polyamine transport. Thus, there is a need to develop drugs that inhibit polyamine transport to use in combination with DFMO. Surprisingly, little is known about the polyamine transport system in humans and other eukaryotes. Understanding ...


The Dlk1-Meg3 Locus In Malignant Cells Of Proposed Primordial Germ Cell Origins., Zachariah Payne Sellers Aug 2017

The Dlk1-Meg3 Locus In Malignant Cells Of Proposed Primordial Germ Cell Origins., Zachariah Payne Sellers

Electronic Theses and Dissertations

Primordial germ cells (PGCs) are hypothesized to deposit hematopoietic stem cells (HSCs) along their migration route through the embryo during the early stages of embryogenesis. PGCs also undergo global chromatin remodeling, including the erasure and reestablishment of genomic imprints, during this migration. While PGCs do not spontaneously form teratomas, their malignant development into germ cell tumors (GCTs) in vivo is often accompanied by the retention of hypomethylation at the IGF2-H19 imprinting control differentially methylated region (DMR). Previous studies in bimaternal embryos determined that proper genomic imprinting at two paternally imprinted loci was necessary for their growth and development: Igf2-H19 and ...


Cannabinoid Receptor 2 And C-X-C Chemokine Receptor 4 Interact To Abrogate Cxcl12-Mediated Cellular Response, Christopher James Coke May 2017

Cannabinoid Receptor 2 And C-X-C Chemokine Receptor 4 Interact To Abrogate Cxcl12-Mediated Cellular Response, Christopher James Coke

Electronic Theses & Dissertations Collection for Atlanta University & Clark Atlanta University

The expression of C-X-C Chemokine Receptor 4 (CXCR4) has been correlated with increased metastatic potential of cancer cells. CXCR4 increases tumor malignancy by encouraging tumors cells to migrate to distal organs expressing its cognate ligand, CXCL12, facilitating metastasis. Thus, targeting the CXCR4/CXCL12 signaling axis provides a good strategy to inhibit the metastatic spread of tumor cells and slow cancer progression. Various studies suggest that cannabis may have anti-proliferative as well as anti-metastatic properties, though a biochemical mechanism describing how this occurs has yet to be discovered. Our lab has confirmed that agonist-bound CXCR4 and agonist-bound Cannabinoid Receptor 2 (CB2 ...


B7h6: A Cancer Biomarker For The Development Of Novel Immunotherapy Approaches, Mariana Phillips May 2017

B7h6: A Cancer Biomarker For The Development Of Novel Immunotherapy Approaches, Mariana Phillips

Seton Hall University Dissertations and Theses (ETDs)

Cancer-based immunotherapy has led the evolution of biologics that can stimulate immune responses towards tumor eradication. The synthesis of small to intermediate size molecules with the targeting and effector functions of mAb may represent a novel class of immunotherapeutics that may overcome the limitations of their biological counterparts.Towards this objective, B7H6 has been identified as a protein ligand localized on the cell surface of transformed tumor cells. B7H6 binds specifically to the activating receptor NKp30, constitutively expressed on all resting and active NK cells. Upon ligand:receptor binding, B7H6 triggers NK cell activation and release of chemokines and pro-inflammatory ...


Investigating E2f Independent Cell Cycle Control And Tumor Suppression By Prb, Michael J. Thwaites Apr 2017

Investigating E2f Independent Cell Cycle Control And Tumor Suppression By Prb, Michael J. Thwaites

Electronic Thesis and Dissertation Repository

Cellular division is primarily controlled at the G1 to S-phase transition of the cell cycle by the retinoblastoma tumor-suppressor protein (pRB). The ability of pRB to restrict S-phase entry is primarily attributed to the repression of E2F transcription factors required to upregulate cell cycle target genes necessary for cellular division. Interestingly, while pRB is disrupted in the vast majority of human cancers, mutations typically target upstream regulators of pRB leading to inactivation through hyperphosphorylation. The rarity of direct pRB mutations suggests that the regulation of the cell cycle by pRB may involve additional mechanisms outside of E2F repression, as this ...


Silica Nanoparticles For The Delivery Of Dna And Rnai In Cancer Treatment, Michael Aaron Vrolijk Jan 2017

Silica Nanoparticles For The Delivery Of Dna And Rnai In Cancer Treatment, Michael Aaron Vrolijk

Graduate College Dissertations and Theses

DNA and interfering RNA (RNAi) – short interfering RNA (siRNA) and micro RNA (miRNA) – are promising new cancer therapies, especially for drug resistant lines. However, they require a delivery system in vivo to prevent degradation and off target effects. Silica based nanoparticles, both solid and mesoporous, are a promising option due to their biocompatibility, ease of preparation and morphology control, reproducibility, and facile addition of functional groups including targeting ligands.

After a brief introduction to cancer treatment and review of the current nanoparticle treatments undergoing clinical trials, this thesis details the many methods explored over the past ten years to fine-tune ...


Transcriptional Regulation In Cancer-Driven Cellular Stress And Functional Specialization Of A Myosin Heavy Chain Protein, Myh7b, Veronica L. Dengler Jan 2017

Transcriptional Regulation In Cancer-Driven Cellular Stress And Functional Specialization Of A Myosin Heavy Chain Protein, Myh7b, Veronica L. Dengler

Molecular, Cellular, and Developmental Biology Graduate Theses & Dissertations

Cancer is a disease of dysregulated gene expression in which many developmental programs are hijacked. One such program is the cellular response to hypoxia, or low oxygen stress. Hypoxia-inducible factors (HIF) govern the cell’s response to this stressor. While much is known about the transcriptional programs HIF directs, comparably little is known about the transcriptional regulation enabling the progression of this response. In the first two chapters of this thesis, I report on the current state of knowledge of the HIF transcriptional program and present new evidence for the role of the conserved coactivator, TIP60, on HIF1A, the primary ...


Tumor Interferon Signaling Initiates And Sustains A Multigenic Resistance Program To Immune Checkpoint Blockade, Joseph Lawrence Benci Jan 2017

Tumor Interferon Signaling Initiates And Sustains A Multigenic Resistance Program To Immune Checkpoint Blockade, Joseph Lawrence Benci

Publicly Accessible Penn Dissertations

Therapeutic blockade of the CTLA4 and/or PD1 immune checkpoint pathways has resulted in significant anti-tumor responses in broad variety of cancer types, but resistance is common. Using mouse models of metastatic melanoma and breast cancer in combination with CRISPR/Cas9 to selectively delete genes in our tumor cells, we demonstrate that prolonged interferon signaling orchestrates PDL1-dependent and PDL1-independent resistance to immune checkpoint blockade (ICB), and to combinations such as radiation plus anti-CTLA4. Furthermore, we show that this interferon driven resistance mechanism primarily occurs in ICB resistant tumors and not in ICB responsive tumors. Persistent type II interferon signaling allows ...


Role Of Erk3 In Regulating Rhogdi1-Paks Signaling Axis, Hitham Abdulrahman Aldharee Jan 2017

Role Of Erk3 In Regulating Rhogdi1-Paks Signaling Axis, Hitham Abdulrahman Aldharee

Browse all Theses and Dissertations

Extracellular signal-regulated kinase 3 (ERK3) is an atypical protein kinase of the mitogen-activated protein kinase (MAPK) family. In comparison to well-investigated ERK1/2 (classical) MAPKs, much less has been discovered about ERK3 signaling and its cellular functions. Recent studies have shown that ERK3 is overexpressed in various types of cancers such as lung cancer and breast cancer and that ERK3 promotes cancer cell migration and invasion. How ERK3 regulates cancer cell motility and invasiveness, however, is still largely unknown. RhoGTPases, including Rho, Cdc42 and Rac1, play critical roles in regulating cell motility and invasiveness through activating downstream effectors such as ...


Epithelial-Mesenchymal Crosstalk Influences Cancer-Related Cell Behavior: A 3d Lung Alveolus-Fibroblast Co-Culture System, Jessica Kole Hall Jan 2017

Epithelial-Mesenchymal Crosstalk Influences Cancer-Related Cell Behavior: A 3d Lung Alveolus-Fibroblast Co-Culture System, Jessica Kole Hall

Undergraduate Honors Theses

Lung cancer is a devastating disease that kills more individuals in the United States than any other cancer. The tumor microenvironment is increasingly recognized as playing a major role in the progression of cancer. Thus, studying the interactions among lung cancer cells, non-malignant cells and the surrounding matrix is critical for understanding and treating lung cancer. Three-dimensional in vitro co-culture systems allow for tissue-relevant platforms that better recapitulate the native cell environment. In this work, we employed a cyst templating technique to culture alveolar epithelial cells on photodegradable microspheres and subsequently encapsulated the cell-covered spheres within poly(ethylene glycol) (PEG ...


Comprehensive Molecular Characterization Of Human Nodal, Scott D. Findlay Dec 2016

Comprehensive Molecular Characterization Of Human Nodal, Scott D. Findlay

Electronic Thesis and Dissertation Repository

Nodal and related ligands are highly conserved members of the TGF-beta superfamily with well-established and essential roles in the early embryonic development of vertebrates, and in cell fate decisions in human embryonic stem (hES) cells. Aberrant NODAL signaling also generally promotes pro-tumourigenic phenotypes and the progression of a wide array of human cancers. Despite being pursued as a potential therapeutic target, many aspects of NODAL’s molecular biology remain poorly understood. This thesis provides a comprehensive characterization of gene expression from the human NODAL locus at multiple levels. First, an intronic NODAL SNP known as rs2231947 was found to be ...


Characterization Of The Catalytic Ck2 Subunits With Substitutions At Residues Involved In Inhibitor Binding, Paul Desormeaux Sep 2016

Characterization Of The Catalytic Ck2 Subunits With Substitutions At Residues Involved In Inhibitor Binding, Paul Desormeaux

Electronic Thesis and Dissertation Repository

CK2 is a constitutively active, ubiquitously expressed and pleiotropic serine/threonine protein kinase that is implicated in many cellular functions including tumorigenesis. CK2 has two catalytic subunits, CK2a and CK2a’, that carry out its function in the cell. Previous studies have indicated that inhibitor-refractory mutants have been effective in recovering residual CK2 activity, in the presence of inhibitors, when compared to wild type CK2. Based on these observations, inhibitor-refractory mutants were created for both CK2a and CK2a’ and tested with various concentrations with two CK2-specific inhibitors, CX-4945 and inhibitor VIII. The CK2a triple mutant (V66A/I174A/H160D) was tested in ...


Investigating The Roles Of Δnp63 As A Suppressor Of Migration, Invasion, And Metastasis, Ramon E. Flores Gonzalez Aug 2016

Investigating The Roles Of Δnp63 As A Suppressor Of Migration, Invasion, And Metastasis, Ramon E. Flores Gonzalez

UT GSBS Dissertations and Theses (Open Access)

Cancer is one of the leading causes of death and disease in the world. Considerable resources are spent to study and understand cancer, with the hope of developing new treatments and eventually cures that will help millions of people. Efforts to understand cancer are hindered by its inherent complexity and instability. Nonetheless, understanding the basics of tumor development and progression are the key to focused on studying the role of ΔNp63 in cancer, a p53 family member known to be involved in epithelial development, microRNA biogenesis, and stem cell maintenance. Using the strength of in vivo mouse models, we found ...


Cell Cycle Arrest By Tgfß1 Is Dependent On The Inhibition Of Cmg Helicase Assembly And Activation, Brook Samuel Nepon-Sixt Jun 2016

Cell Cycle Arrest By Tgfß1 Is Dependent On The Inhibition Of Cmg Helicase Assembly And Activation, Brook Samuel Nepon-Sixt

Graduate Theses and Dissertations

Tumorigenesis is a multifaceted set of events consisting of the deregulation of several cell-autonomous and tissue microenvironmental processes that ultimately leads to the acquisition of malignant disease. Transforming growth factor beta (TGFß) and its family members are regulatory cytokines that function to ensure proper organismal development and the maintenance of homeostasis by controlling cellular differentiation, proliferation, adhesion, and survival, as well as by modulating components of the cellular microenvironment and immune system. The pleiotropic control by TGFß of these cell intrinsic and extrinsic factors is intimately linked to the prevention of tumor formation, the specifics of which are dependent on ...


Characterization Of Numb As A Regulator Of Anaplastic Lymphoma Kinase, Ran Wei Jun 2016

Characterization Of Numb As A Regulator Of Anaplastic Lymphoma Kinase, Ran Wei

Electronic Thesis and Dissertation Repository

Cellular events rely on protein-protein interactions that are often mediated by modular domains which recognize particular sequence motifs in binding partners. The NUMB protein is the first described cell fate determinant and multifaceted adaptor that is involved in a wide variety of cellular events. NUMB mainly mediates protein interactions via its modular PTB domain. Here we present a systematic investigation of the NUMB-PTB interactome by employing an integrative strategy combining both protein and peptide arrays. We profiled NUMB-PTB binding specificity and interacting proteins genome-wide. The receptor tyrosine kinases (RTKs) are found highly enriched in the interactome, raising the possibility that ...


Immune Modulating Functions By Soypeptide Lunasin In Cancer Immunotherapy, Chun-Yu Tung May 2016

Immune Modulating Functions By Soypeptide Lunasin In Cancer Immunotherapy, Chun-Yu Tung

Open Access Dissertations

Chemotherapy is currently the mainstay of treatment for most cancer patients. Despite its efficacy in eliminating cancer cells, a high percentage of chemotherapy patients eventually relapse or suffer progression of the disease. Immunosurveillance is capable of recognizing and eliminating continuously arising transformed mutant cells, and thus cancer immunotherapy is one of the emerging therapeutic strategies that harnesses the power of the immune system to eradicate chemotherapy-resistant cancerous cells. However, the adverse side effects of chemotherapy impede the therapeutic effects of immunotherapy. Our previous studies demonstrate that lymphoma patients are refractory to clinical immunotherapy because of chemotherapy-induced immune dysfunction. In addition ...


Is Hif-1Α Required For V-Atpase-Dependent Regulation Of Glycolytic Enzymes?, Tyler Northrup Apr 2016

Is Hif-1Α Required For V-Atpase-Dependent Regulation Of Glycolytic Enzymes?, Tyler Northrup

Life and Environmental Sciences Undergraduate Theses

Vacuolar-ATPase (V-ATPase) is frequently up-regulated in tumors and tumor cell lines where it contributes to tumorigenic phenotypes, including the Warburg Effect (e.g. the phenomenon where glycolysis is preferred over oxidative phosphorylation (Vander Heiden et al. 2009)). The preferential use of glycolytic metabolism favored by tumor cells may be caused by at least two factors (Vander Heiden et al. 2009). First, the metabolic intermediates generated by the citric acid (TCA) cycle are used in a variety of anabolic pathways in the cell, and may supply a ready source of intermediate buildingblocks for biosynthetic processes. Second, hypoxia observed in some tumors ...


Alternative Regulation Of Myc In Lung Cancer, Patrick N. Backman Mar 2016

Alternative Regulation Of Myc In Lung Cancer, Patrick N. Backman

Open Access Theses

Lung cancer is the leading cause of cancer deaths in the United States, accounting for 27% of all cancer induced deaths1. In an attempt to create a effective targeted therapy for the treatment of lung cancer, a strategy used to treat an activated KrasG12D/+;p53 R172H/+ transgenic lung cancer mouse model was to deliver a known tumor suppressive microRNA (miRNA) to stop tumor growth. The tumor suppressive miRNA let-7 was lentivirally delivered in the form of its primary transcript, pri-let-7a-1, and resulted in increased lung size and inflammation compared to lungs exposed to a control lentivirus. It was ...


Modulation Of Antitumor Immunity By The Mek Inhibitor Trametinib: Implications For Targeted Therapy Of Cancer, Michael J. Allegrezza Jan 2016

Modulation Of Antitumor Immunity By The Mek Inhibitor Trametinib: Implications For Targeted Therapy Of Cancer, Michael J. Allegrezza

Publicly Accessible Penn Dissertations

Through rational drug design, much progress has been made to develop small molecules that specifically inhibit the oncogenic signaling pathways driving malignant growth. However, the normal function of immune cells depends upon many of the same pathways inhibited by such targeted cancer therapies. Because the immune system can influence the growth of many cancers, I hypothesized that most small molecule inhibitors would have activity on leukocytes relevant in cancer, and this activity would contribute to their antitumor mechanisms. In order to test this hypothesis, I first screened a panel of over 40 small molecule inhibitors for their activity on proliferating ...


Interplay Between P53 And Epigenetic Pathways In Cancer, Jiajun Zhu Jan 2016

Interplay Between P53 And Epigenetic Pathways In Cancer, Jiajun Zhu

Publicly Accessible Penn Dissertations

The human TP53 gene encodes the most potent tumor suppressor protein p53. More than half of all human cancers contain mutations in the TP53 gene, while the majority of the remaining cases involve other mechanisms to inactivate wild-type p53 function. In the first part of my dissertation research, I have explored the mechanism of suppressed wild-type p53 activity in teratocarcinoma. In the teratocarcinoma cell line NTera2, we show that wild-type p53 is mono-methylated at Lysine 370 and Lysine 382. These post-translational modifications contribute to the compromised tumor suppressive activity of p53 despite a high level of wild-type protein in NTera2 ...


With Or Without You: Studying The Requirement Of P53 For Anti-Cancer Responses To Nuclear Export Inhibitors, Andrea E. Doak Jan 2016

With Or Without You: Studying The Requirement Of P53 For Anti-Cancer Responses To Nuclear Export Inhibitors, Andrea E. Doak

Undergraduate Honors Theses

Exportin-1 (XPO-1) is responsible for the movement of cargo proteins out of the nucleus and into the cytoplasm. Selective inhibitors of nuclear export (SINE) bind XPO-1 at cysteine-528, which results in the sequestration of cargo proteins in the nucleus. SINE drugs are currently being developed and tested in the treatment of many types of cancers. One of the cargos, p53 may play an important role in the efficacy of SINE. To test the necessity of p53 in the action of SINE drugs, matched pairs of cell lines with wildtype or functionally disrupted p53 were analyzed for differences in their cell ...


Genomic Aberrations At The 3q And 14q Loci: Investigation Of Key Players In Ovarian And Renal Cancer Biology, Punashi Dutta Jan 2015

Genomic Aberrations At The 3q And 14q Loci: Investigation Of Key Players In Ovarian And Renal Cancer Biology, Punashi Dutta

Graduate Theses and Dissertations

Genomic aberrations are primary contributors to the pathophysiology of cancer [11]. Dysregulated expression of genes located within these aberrations are important predictors of chemoresistance, disease prognosis, and patient outcome [12]. This dissertation is focused on understanding the regulation and/or functions of specific genes located at dysregulated genomic regions such as 3q26 and 14q32 in the biology of ovarian and renal cancer, respectively.

Serous epithelial ovarian cancer (EOC) manifest amplification at the 3q26.2 locus [2], an observation consistent with the cancer genome atlas (TCGA) [13]. The most amplified gene in this region is EVI1 which has been extensively studied ...


Identification Of Novel Microrna Targets And Tumor Suppressive Functions Of Mir-203 In Murine Skin, Kent Augustus Riemondy Jr. Jan 2015

Identification Of Novel Microrna Targets And Tumor Suppressive Functions Of Mir-203 In Murine Skin, Kent Augustus Riemondy Jr.

Molecular, Cellular, and Developmental Biology Graduate Theses & Dissertations

miRNAs are small non-coding RNAs, approximately 22 nucleotide in length, that mediate post-transcriptional repression of target mRNAs. Since their discovery in mammals in the early 2000s, miRNAs have been intensely studied and determined to be an important mechanism to regulate gene expression in diverse biological processes. In human cancers, miRNAs are known to act as tumor suppressors or oncogenes and are being actively explored as a possible mechanism for therapeutic intervention. In the mouse, multistage skin carcinogenesis is a well-established model for studying tumor development however the functions of miRNAs in this model are poorly understood.

The Ras oncogene was ...


Adeno-Associated Viral Vector-Driven Expression Of Coagulation Proteins For Treatment Of Hemophilias And Cancer, Julie Marie Crudele Jan 2015

Adeno-Associated Viral Vector-Driven Expression Of Coagulation Proteins For Treatment Of Hemophilias And Cancer, Julie Marie Crudele

Publicly Accessible Penn Dissertations

Treatment of hemophilia, which involves infusion of the missing clotting factor, is often hindered by the development of neutralizing antibodies to the replaced clotting factor. We utilized liver-directed AAV gene therapy to tolerize outbred hemophiliac dogs with pre-existing anti-factor VIII and IX antibodies and to treat their underlying hemophilia. Additionally, we sought to shed light on the immunologic mechanisms responsible for this tolerization. Staining for CD4+CD25+FoxP3+ T cells and cytokine profiles of treated dogs suggest that induced Tregs are at least partially responsible for inducing and maintaining tolerance.

The second part of the dissertation attempts to determine the ...


Nitric Oxide Synthase Activity And Its Modulation In The Treatment Of Colorectal Cancer, Asim Alam Jan 2015

Nitric Oxide Synthase Activity And Its Modulation In The Treatment Of Colorectal Cancer, Asim Alam

Theses and Dissertations

The American Cancer Society estimates more than 141,000 new cases of and about 50,000 deaths from colorectal cancer every year. Treatment options include surgery, radiation therapy and targeted therapies such as anti-angiogenics. However, no therapies address the key driving factor of colorectal cancer: inflammation. It is well known that chronic inflammatory conditions such as Crohn’s Disease, ulcerative colitis, diabetes, obesity and cigarette smoking all elevate the risk of developing colorectal cancer. One of the hallmarks of chronic inflammation is the elevated levels of reactive oxygen/nitrogen species (ROS/RNS). A primary source of these ROS/RNS is ...


Novel Posttranslational Modification In Lkb1 Activation And Function, Szu-Wei Lee Dec 2014

Novel Posttranslational Modification In Lkb1 Activation And Function, Szu-Wei Lee

UT GSBS Dissertations and Theses (Open Access)

Cancer cells display dramatic alterations in cellular metabolism to meet their needs of increased growth and proliferation. In the last decade, cancer research has brought these pathways into focus, and one emerging issue that has come to attention is that many oncogenes and tumor-suppressors are intimately linked to metabolic regulation (Jones and Thompson, 2009). One of the key tumor-suppressors involved in metabolism is Liver Kinase B1 (LKB1). LKB1 is the major upstream kinase of the evolutionarily conserved metabolic sensor—AMP-activated protein kinase (AMPK). Activation of the LKB1/AMPK pathway provides a survival advantage for cells under energy stress. LKB1 forms ...


Sirna Targeting Of Thymidylate Synthase, Thymidine Kinase 1 And Thymidine Kinase 2 As An Anticancer Therapy: A Combinatorial Rnai Approach, Christine Di Cresce Apr 2014

Sirna Targeting Of Thymidylate Synthase, Thymidine Kinase 1 And Thymidine Kinase 2 As An Anticancer Therapy: A Combinatorial Rnai Approach, Christine Di Cresce

Electronic Thesis and Dissertation Repository

Thymidylate synthase (TS) is the only de novo source of thymidylate (dTMP) for DNA synthesis and repair. Drugs targeting TS protein are a mainstay in cancer treatment but off-target effects and toxicity limit their use. Cytosolic thymidine kinase (TK1) and mitochondrial thymidine kinase (TK2) contribute to an alternative dTMP-producing pathway, by salvaging thymidine from the tumour milieu, and may modulate resistance to TS-targeting drugs. We have previously shown that TS antisense molecules (oligodeoxynucleotides, ODNs, and small interfering siRNA, siRNA) sensitize tumour cells, both in vitro and in vivo, to TS targeting drugs. As both TS and TKs contribute to cellular ...