Medical Cell Biology Commons^™

The Impact Of Glucose Exposure On Organic Cation Transporters (Oct) Function In A Corneal Epithelial Cell Line, David A. Garza

Theses & Dissertations

Organic cation transporters (OCT) facilitate the movement of neurochemicals and medications, contribute to the removal of cellular waste, and facilitate neuronal communication. Three subtypes of these high-capacity, low-affinity transporters (OCT1, OCT2, and OCT3) are differently expressed in peripheral tissues such as the liver, kidneys, as well as the central nervous system. OCTs are also expressed in ocular tissues. Chronic hyperglycemia is a complication commonly associated with diabetes that can lead to ocular diseases such as diabetic keratopathy, which affects the cornea. In this project, we expose immortalized human corneal epithelial cells (HCE-S) to various glucose concentrations to study their impact …

Restoring Translational Control With Novel Small Molecule Activators Of Pp2a In Cancer Cells, Kayla A. Jonas

Theses & Dissertations

Hyperactivation of eIF4E-dependent translation in tumor cells is required for robust expression of oncogenic proteins and maintenance of the transformed phenotype. eIF4E binds to the 7-methylguanylate structure at the 5’ end of cellular mRNAs and nucleates the formation of the translation initiation complex, eIF4F, which recruits the preinitiation complex and resolves secondary structure in the mRNA. The ability of eIF4E to promote eIF4F assembly is negatively regulated by the translational repressor, 4E-BP1, and tumorigenesis depends on functional inactivation of 4E-BP1. A major mechanism of 4E-BP1 inactivation involves inhibitory phosphorylation by mTOR which prevents eIF4E binding. Functional inactivation can also occur …

Understanding The Role Of Mastl In Colon Homeostasis And Colitis-Associated Cancer Development, Kristina Pravoverov

Theses & Dissertations

Colitis-associated cancer (CAC) is the most devastating complication of longstanding inflammatory bowel disease (IBD). Understanding the mechanisms underlying the switch from damage-repair to dysplasia in IBD is critical for identifying novel therapies to facilitate mucosal healing while mitigating CAC risk. Microtubule-associated serine-threonine kinase-like (MASTL), though crucial in cell growth and repair, is upregulated in sporadic colorectal cancer and CAC. This study sought to delineate the role of MASTL in colitis and CAC development.

First, we examined whether MASTL is associated with colitis and recovery. Review of publicly available data found significant elevation of MASTL and interleukin (IL)-22 in biopsies from …

The Co-Oncogenic Function Of Ecdysoneless Protein With Erbb2 In Mammary Epithelial Cells, Benjamin B. Kennedy

Theses & Dissertations

The Ecdysoneless (ECD) protein is highly evolutionarily conserved and ubiquitously expressed across human tissues. ECD has established roles in cell cycle regulation, embryogenesis, cell survival, and RNA biogenesis. ECD mRNA and protein are overexpressed in breast cancer, and its overexpression correlates with poor patient survival, especially in ErbB2/HER2-positive breast cancer. This thesis work investigates the co-oncogenic role of ECD in ErbB2-driven oncogenesis using immortalized mammary epithelial cells. Here, we show that ECD and ErbB2 overexpression in immortalized human mammary epithelial cells increases cancer traits, such as invasion, migration, and anchorage independent growth. Significantly, ECD+ErbB2 co-overexpression further enhanced all oncogenic traits. …

Development Of Combination Therapy Strategies To Treat Cancer Using Dihydroorotate Dehydrogenase Inhibitors, Nicholas Mullen

Theses & Dissertations

Cancer cells require supraphysiologic levels of nucleotide triphosphates to fuel their malignant behaviors, including uncontrolled proliferation, immune evasion, metastasis, and therapy resistance. This requirement is met by hyperactive flux through the de novo pyrimidine and de novo purine pathways. Dihydroorotate dehydrogenase (DHODH) is an essential enzyme in the de novo pyrimidine pathway that can be targeted by FDA approved and experimental drug compounds. A robust body of preclinical evidence, encompassing hundreds of independent studies over several decades, demonstrates impressive activity of DHODH inhibitors in animal models of cancer. Paradoxically, however, all clinical trials to date have failed to demonstrate efficacy …

Regulation Of Pancreatic Cancer Progression By Micronutrients, Chunbo He

Theses & Dissertations

Cancer cells rely on altered metabolism to support their uncontrolled proliferation under harsh conditions. Understanding the mechanisms of how metabolic alterations support tumor growth may provide a way to enhance current therapies. Vitamins are micronutrients that our body needs in small quantities but are essential for health maintenance. A number of metabolic processes relevant to cancer initiation and progression are also regulated by vitamins. Here, our studies showed that pancreatic ductal adenocarcinoma (PDAC) cells display an aberrant metabolism of vitamin B6 (VB6) to support their fast proliferation. VB6 was highly demanded and rapidly metabolized by PDAC cells. Depletion of VB6 …

Gene Expression Profiling Of Mapk Pathway Inhibitor Resistance In Cutaneous Melanoma: Can Bioinformatics Be Used To Select Better Melanoma Cell Lines?, Stephen Luebker

Theses & Dissertations

Melanoma is the deadliest form of skin cancer, and incidence has continued to increase. Half of all melanomas have a BRAF V600E mutation and respond to MAPK pathway inhibitors, including BRAF inhibitor therapy or BRAF/MEK inhibitor combination therapy, but nearly all patients develop treatment resistance. Melanoma cell lines produce variable results as models of MAPK pathway inhibitor resistance. To better understand how the genomic similarity of a melanoma cell line to patient-derived tumors affects resistance mechanisms, differences in DNA mutations and copy-number alterations were compared between melanoma cell lines profiled by the Cancer Cell Line Encyclopedia and cutaneous melanoma tumors …

The Role Of Vgll4 And Mark2-Hdac Axis In Mitosis And Cancer, Yongji Zeng

Theses & Dissertations

The Hippo pathway is an evolutionarily conserved signaling pathway that plays important roles in stem cell biology, tissue homeostasis, and cancer development. The Hippo core signaling pathway features a kinase cascade consisting of mammalian sterile-20 like protein 1/2 (Mst1/2) and large tumor suppressor 1/2 (Lats1/2). Inactivation of the Hippo pathway is correlated with the promotion of proliferation and anti-apoptosis through activation of the transcriptional co-activator Yes-associated protein (YAP). YAP functions through binding with TEA-domain transcription factors (TEAD1–4) to activate target genes.

Vestigial-like 4 (Vgll4) functions as a transcriptional co-repressor in the Hippo-Yes associated protein (YAP) pathway. Vgll4 inhibits cell proliferation …

Molecular Mechanisms Of Manganese Porphyrin Compounds In The Prevention Of Radiation-Induced Fibrosis, Shashank Shrishrimal

Theses & Dissertations

Radiation therapy is frequently used as a treatment strategy for prostate cancer patients, which leads to several side effects due to damage to health tissue around the tumor and the development of radiation-induced fibrosis (RIF). Manganese (III) meso-tetrakis (N-ethylpyridinium-2-yl) porphyrin (MnTE-2-PyP or T2E or BMX-010) and other similar manganese porphyrin compounds that scavenge superoxide molecules have been demonstrated to be effective radioprotectors and prevent the development of RIF. However, understanding of the radioprotective molecular pathway associated with these compounds remains limited. Recent RNA-sequencing data from our laboratory revealed that MnTE-2-PyP treatment may activate the nuclear factor erythroid 2-related factor 2 …

The Role Of Ros In The Progression And Treatment Of Castration-Resistant Prostate Cancer, Dannah R. Miller

Theses & Dissertations

Prostate cancer is the second leading cause of cancer-related deaths in U.S. men, primarily due to the development of castration-resistant (CR) prostate cancer (PCa), of which there are no effective treatment options. Reactive oxygen species (ROS) plays a critical role in prostate carcinogenesis, including the progression of the CR PCa phenotype. ROS regulates both cell proliferation and apoptosis; a moderate increase in ROS can promote proliferation; however, a substantial rise in ROS levels will result in apoptosis. Oxidase p66Shc is elevated in clinical PCa cells and has been associated with a metastatic phenotype of CR PCa cells, promoting PCa cell …

Muc4 Based Immunotherapy For Pancreatic Cancer, Kasturi Banerjee

Theses & Dissertations

Pancreatic Cancer (PC) is a lethal disease claiming approximately 45000 lives in the US in 2018, and it establishes an elaborate immunosuppressive tumor microenvironment that aids in disease pathogenesis. Immunotherapy has emerged as a strategy to target tumor cells by reprogramming patient’s immune system. Challenges present in PC immunotherapy are: i) identifying a tumor-associated antigen that could be targeted, ii) identifying adjuvants that could efficiently deliver antigens, iii) eliciting robust anti-tumor responses and iv) overcoming peripheral tolerance and immunosuppression elicited by the tumor.

Firstly, we detected circulating autoantibodies to MUC4 present in PC patients and observed that IgM autoantibodies to …

The Role Of Yes-Associated Protein 1 In Ovarian Physiology And Pathology, Xiangmin Lv

Theses & Dissertations

Ovarian granulosa cells are the major somatic components of the ovarian follicle. Proper proliferation and differentiation of ovarian granulosa cells are essential for successful follicle development. Accumulating evidence indicates that the Hippo-YAP signaling pathway plays critical roles in both development and tumorigenesis of several organs. The present study aims to investigate the role of Yes-associated protein 1 (YAP) in ovarian granulosa cell proliferation, differentiation, and malignant transformation. At first, we found that nuclear YAP (active) was highly expressed in proliferative granulosa cells, whereas cytoplasmic YAP (inactive) was detected mainly in terminally-differentiated luteal cells. Further studies suggested that endogenous YAP activity …

Novel Therapeutic Strategies For Treatment Of Castration-Resistant Prostate Cancer, Matthew A. Ingersoll

Theses & Dissertations

Prostate cancer (PCa) remains the most commonly diagnosed solid tumor and is the third leading cause of cancer-related death in United States men. While androgen deprivation therapy is the current standard-of-care treatment for metastatic PCa, most patients eventually relapse and develop castration-resistant (CR) tumors, for which there is currently no effective treatment. Therefore, synthesis of novel therapeutic agents and identification of alternative target proteins are necessary to improve treatment. Herein, I investigate the efficacy of novel imidazopyridine and statin derivatives as alternative therapeutic compounds. These molecules not only inhibit androgen receptor signaling, but also block activation of the AKT axis, …

Understanding The Chondrogenic Potential Of Articular Chondrocytes, Krishna Sarma

Theses & Dissertations

Articular cartilage is a smooth, visco-elastic, aneural, avascular tissue made of water, an exquisitely organized framework of proteoglycans, glycosaminoglycans, and collagen fibrils and articular chondrocytes. It’s beautiful organization and composition provide it with the flexibility and strength to cover, protect and lubricate the ends of long bones in a diarthrodial joint. Cartilage homeostasis relies on articular chondrocytes to translate the mechanical forces of daily activity into efficient remodeling of the extracellular matrix. Age, joint injury, or other insulting factors can progressively incapacitate articular chondrocytes, resulting in cartilage lesions that devolve to degenerative joint disease. Therefore, the central idea explored in …

Ehd1 As A Positive Regulator Of Macrophage Colony-Stimulating Factor-1 Receptor, Luke R. Cypher

Theses & Dissertations

The master regulator of the macrophage development, differentiation, proliferation, survival, phagocytosis, cytokine secretion, motility, adhesion, migration, and spreading is the receptor tyrosine kinase (RTK) colony stimulating factor-1 receptor (CSF-1R). Aberrant CSF-1R signaling is present amongst a variety of highly prevalent and devastating human diseases in the United States such as atherosclerosis, cancer, inflammatory bowel disease, arthritis, and neuro-demyelination/neuro-degeneration. A better understanding of basic mechanisms that govern macrophage development and function is of vital importance in treating patients afflicted with these conditions/diseases. CSF-1R presentation on the macrophage cell surface is a required precursor for CSF1- induced RTK dimerization (activation) and downstream …

Epacs: Epigenetic Regulators That Affect Cell Survival In Cancer., Catherine Murari

Theses & Dissertations

Cyclic adenosine monophosphate (cAMP) is a second messenger responsive to many external stimuli, playing an important role in cellular gene expression, metabolism, migration, differentiation, hypertrophy, apoptosis and secretion. All of these cellular functions are important in many diseases including cancer. Most of its effects were initially attributed to the classical protein kinase A (PKA) protein, but cellular functions such as proliferation and migration were found to be PKA independent and dependent on the newly discovered exchange proteins directly activated by cAMP (EPACs). EPACs are single polypeptides that primarily function as guanine exchange factors (GEFs) for Rap proteins that allow the …

The Role Of Glutaminase 1 In Hiv-1 Associated Neurocognitive Disorders And In Brain Development, Yi Wang

Theses & Dissertations

Glutaminase is the enzyme that converts glutamine into glutamate, which serves as a key excitatory neurotransmitter and one of the energy providers for cellular metabolism. Glutamate is essential for proper brain functioning but at excess levels, it is neurotoxic and has a key role in the pathogenesis of various neurodegenerative diseases, including HIV-1 associated neurocognitive disorders (HAND). However, the detailed mechanism of glutamate-mediated neurotoxicity remains unclear. In part I, we identified the regulation of glutaminase 1 (GLS1) in the central nervous system (CNS) of HAND animal models including HIV-Tat transgenic (Tg) mouse and HIVE-SCID mouse, since GLS1 is the dominant …