Cancer Biology Commons^™

Cellular Glycosphingolipid Imbalance Modulates Emt In Cancer Cells, Laura E. Clark, Amanda Dickinson, Santiago Lima

Undergraduate Research Posters

Sphingolipids are key components of the plasma membrane and are regulators of complex biological processes often altered in cancer cells. In human tumors, genes of key enzymes that regulate levels of glucosylceramide and lactosylceramide are often amplified. However, it is unknown why these traits are positively selected in transformed cells. In this work, we used CRISPR-Cas9 to knockout two key enzymes amplified in tumors in HeLa and H1703 tumor-derived cell-lines. As expected, the knockout lines had dramatic accumulation of GlcCer and LacCer. However, unexpectedly, they showed significantly decreased in-vitro wound-healing capacity and an almost complete loss of in-vitro extra-cellular matrix …

Dissecting The Role Of Selenoprotein P And Thioredoxin Reductase In Pancreatic Cancer Metabolism, Alyssa A. Abbas

Dissertations, Master's Theses and Master's Reports

Pancreatic ductal adenocarcinoma (PDAC), the fourth leading cause of US cancer-related deaths, has a stark 5-year survival rate of 9%, emphasizing an urgent need for effective therapies. A well-established characteristic of cancer, metabolic dysregulation, presents an opportunity for developing therapies that target specific metabolic susceptibilities inherent in cancer cells. Our recent studies have discovered a susceptibility in PDAC; deprivation of cystine or blocking its uptake by erastin (a cystine transport inhibitor) triggers significant lipid peroxidation, thereby inducing ferroptosis specifically in the mesenchymal subtype of PDAC, but not in the epithelial subtype. This study aims to elucidate the roles of Selenoprotein …

Modulatory Effects Of Deacetylated Sialic Acids On Breast Cancer Resistance Protein-Mediated Multidrug Resistance And Receptor Tyrosine Kinase-Targeted Therapy, Isaac Tuffour

Electronic Theses and Dissertations

Multidrug resistance (MDR) remains a major challenge in cancer treatment, accounting for over 90% of chemotherapeutic failures. Cancers utilize sugar residues to engage in multidrug resistance. The underlying mechanism of action involving glycans, specifically the glycan sialic acid (Sia) and its various functional group alterations, has not been explored. ATP-binding cassette (ABC) transporter proteins, key proteins utilized by cancers to engage in MDR pathways, contain Sias in their extracellular domains. Modulating the expression of acetylated-Sias on Breast Cancer Resistance Protein (BCRP), a significant ABC transporter implicated in MDR, in lung and colon cancer cells directly impacted the ability of cancer …

Cell Signaling And Stress Response In The Yeast Saccharomyces Cerevisiae: A Study Of Snf1, Scott E. Arbet Ii

Graduate Theses, Dissertations, and Problem Reports (ETD)

Saccharomyces cerevisiae are yeast that are unicellular eukaryotic organisms that are well studied as a model organism for understanding fundamental cellular processes. The ability of yeast to sense nutrient availability is crucial for their survival, growth, and reproduction. Yeast cells use various mechanisms to sense and respond to nutrient availability, including transporter-mediated uptake, receptor-mediated signaling, and sensing of metabolites. The subcellular localization of nutrient-sensing components is crucial for yeast function in nutrient sensing and signaling. Protein complexes, such as the AMP-activated protein kinase (AMPK) pathway, in nutrient sensing and response, as well as the downstream effects of these pathways …

Conserved Novel Interactions Between Post-Replicative Repair And Mismatch Repair Proteins Have Differential Effects On Dna Repair Pathways, Anna K. Miller

Theses and Dissertations--Toxicology and Cancer Biology

DNA mismatch repair (MMR) is the DNA repair mechanism that repairs base-base mispairs and small insertions and deletions remaining after replication. MMR is also required for apoptosis after certain types of exogenous DNA damage that result in damage-associated mispairs. The basic MMR mechanism is well understood; however, proteins associated with MMR continue to be identified. The roles of these interacting proteins in MMR are largely unknown. We have identified the yeast protein Rad5 as a novel interactor of the critical MMR proteins Msh2 and Mlh1. Rad5 is a DNA helicase and E3 ubiquitin ligase involved in post-replicative repair. However, to …

Elucidating The Functional Importance Of Peroxiredoxin Iv In Prostate Cancer And Its Secretion Mechanism, Na Ding

Theses and Dissertations--Toxicology and Cancer Biology

Prostate cancer is the most common and second leading cause of cancer death in men. Prevailing theories state that inflammation may drive prostate carcinogenesis via oxidative stress and the generation of reactive oxygen species (ROS) that induce somatic mutagenesis. Since high proliferating cells or cancer cells exhibit aberrant metabolism to satisfy the needs of energy for rapid cell proliferation, they also generate high levels of ROS which stimulates the expression of cellular antioxidants to overcome the dysregulation of redox homeostasis through the regulation of redox-sensitive transcription factors. Among different antioxidants, peroxiredoxin (Prx) family proteins are the highly conserved and mostly …

Novel Mechanisms Of Protein Kinase C Α Regulation And Function, Xinyue Li

Theses & Dissertations

Protein kinase Cα (PKCα) is a member of the PKC family of serine/threonine kinases, which have been implicated in regulation of many cellular processes, including cell proliferation, differentiation, survival, and transformation. A large body of evidence from the Black laboratory and others support an anti-proliferative function of PKCα in normal epithelial tissues, including the intestinal mucosa and endometrial epithelium. PKCα is also tumor suppressive in epithelial cancers, such as colorectal cancer (CRC) and endometrial cancer (EC). However, a major obstacle to harnessing the tumor suppressive functions of PKCα to benefit patients is the widespread loss of PKCα expression in tumors. …

Bis-Indolyl Compounds And The Induction Of Apoptosis In T98g Glioblastoma Multiforme Cells, Margot C. Brown

Seton Hall University Dissertations and Theses (ETDs)

1,1-bis(3’idolyl)-1(aryl)methane compounds (BIM compounds) have been shown to have anti-cancer properties in colon cancer, bladder cancer, and leukemia cells. The purpose of this work was to determine if BIM compounds could be an effective treatment of glioblastoma multiforme. Sulforhodamine B (SRB) assays showed that 20µM of the BIM compounds could inhibit cellular proliferation of the T98G glioblastoma multiforme cell line over 72 hours. Then immunoblotting was used to analyze the molecular pathway induced by BIM compounds. An increase in the expression of both BAX and cleaved caspase 3 suggest BIM compounds activate programmed cell death, or apoptosis in glioblastoma cells. …

Determining The Roles Of The Oligomerization And C-Terminal Domains In Mutant P53 Gain-Of-Function Activities, George K. Annor

Dissertations, Theses, and Capstone Projects

The tumor suppressor p53 (TP53) gene is often mutated in cancer, with missense mutations found in the central DNA binding domain, and less often in the oligomerization domain (OD) and C-terminal domain (CTD). The OD and CTD have been found to be critical for the tumor suppressor functionality of wild-type p53 (wtp53). Specific missense mutations in the DNA binding domain have been found to confer new gain-of-function (GOF) activities. Mutations that destabilize tetramer formation, or deletion of key lysine residues within the CTD, downregulate the ability of wtp53 to transactivate (increase the rate of transcription of) its target …

Post-Transcriptional Control Of The Epithelial-To-Mesenchymal Transition (Emt) In Ras-Driven Colorectal Cancers, Chaitra Rao

Theses & Dissertations

Colorectal cancer (CRC) originates from epithelial cells lining the colon or rectum of the gastrointestinal tract. Most cancer deaths result from a tumor spreading to distant organs; however epithelial cells do not normally migrate from their tissue of origin. To do so, epithelial cells undergo biochemical changes allowing them to acquire behavior similar to motile mesenchymal cells termed the epithelial-to-mesenchymal transition (EMT), which contributes to tumor invasion and metastasis. Our study demonstrated that CRC cells require a molecular scaffold, Kinase Suppressor of Ras 1 (KSR1), and ERK to promote the EMT-like phenotype through the preferential translation of Epithelial Stromal Interaction …

A Computational Model Of The Line-1 Retrotransposon Life Cycle And Visualization Of Metabolic Networks In 3-Dimensions., Michael D. Martin

Electronic Theses and Dissertations

Computational modeling of metabolic reactions and cellular systems is evolving as a tool for quantitative prediction of metabolic parameters and reaction pathway analysis. In this work, the basics of computational cell biology are presented as well as a summary of physical processes within the cell, and the algorithmic methods used to find time dependent solutions. Protein-protein and enzyme-substrate interactions are mathematically represented via mass action kinetics to construct sets of linear differential equations that describe reaction rates and formation of protein complexes. Using mass action methods, examples of reaction networks and their solutions are presented within the Virtual Cell simulation …

Integrin-Mediated Mechanotransduction Controls Activation Of Yap And Invasive Growth Of Breast Cancer, Xiaobo Wang

Dissertations and Theses (Open Access)

Tumor extracellular matrix (ECM) stiffness is correlated with the aggressiveness of breast cancer. Integrin-mediated adhesion and signaling are crucial for mammary tumorigenesis and tumor progression, in which focal adhesion kinase (FAK) - Src family kinases (SFKs) serves as a hub to relay the mechanical cues from the ECM. We have investigated the mechanisms through which integrin signaling controls mammary tumorigenesis and found that integrin-mediated mechanotransduction controls invasive growth of breast cancer cells in stiff matrices through activation of FAK and YAP. Mechanistic studies revealed that integrin signaling induces - via activation SFKs - tyrosine phosphorylation and inactivation of LATS1 and …

Regulation Of Systemic And Cellular Metabolism In Prostate Cancer By Camkk2 And Elucidation Of Atgl’S Role In Disease Progression, Dominik Awad

Dissertations and Theses (Open Access)

The androgen receptor (AR) is the major driver of prostate cancer; hence, men with progressing disease are treated with androgen deprivation therapy (ADT). However, the majority of patients will relapse within 2-3 years due to multiple AR reactivation mechanisms. Thus, AR and the processes downstream of the receptor remain central drivers of prostate cancer. A direct target of AR is CAMKK2, a gene coding for the serine/threonine kinase Ca^2+/calmodulin-dependent protein kinase kinase 2 (CAMKK2), a protein upregulated in advanced prostate cancer. CAMKK2 modulates many of its pathological effects through the phosphorylation and activation of the 5' AMP-activated …

Grk3 Connects Angiogenesis And Neuroendocrine Differentiation In Prostate Cancer By Activating Hdac2 That Epigenetically Represses Tsp1 And Rest, Samira Naderinezhad

Dissertations and Theses (Open Access)

Prostate cancer (PCa) is the second most frequent cancer and the second leading cause of mortality in men in the United States. Neuroendocrine prostate cancer (NEPC) is the aggressive subset of castration-resistant prostate cancer (CRPC), found in ~20% lethal CRPC. The mechanisms underlying the progression of PCa to NEPC are still largely unclear, and new drug targets are desperately needed. NEPC is highly vascularized (angiogenic) and characterized by high expression of neuroendocrine markers. However, direct molecular links connecting angiogenesis and neuroendocrine differentiation are elusive.

Since epigenetic regulation has been implicated in NEPC progression, we examined expression patterns of 147 epigenetic …

The Role Of The Hypoxia-Inducible Factor 2 In Pancreatic Cancer: Mechanisms Of Tumor Immunosuppression And Intestinal Radioprotection, Carolina Garcia Garcia

Dissertations and Theses (Open Access)

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with dismal prognosis. The only curative option for patients is surgery, but over 80% of patients are not surgical candidates. Unfortunately, PDAC is resistant to the three remaining options. PDAC is characterized by a profoundly hypoxic and immunosuppressive stroma, which contributes to its therapeutic recalcitrance. Alpha-smooth muscle actin+ (αSMA+) cancer-associated fibroblasts (CAFs) are the most abundant stromal component, as well as mediators of stromal deposition. The hypoxia-inducible factors (HIF1 and HIF2) coordinate responses to hypoxia, yet, despite their known association to poor patient outcomes, their functions within the PDAC tumor microenvironment (TME) …

Roles Of Oxidative Stress And Dna Methylation In Cigarette Smoking-Induced Accelerated Acute Myeloid Leukemia Progression, Mary Figueroa

Dissertations and Theses (Open Access)

Acute myeloid leukemia (AML) is a commonly diagnosed cancer in smokers. When current or former smokers have AML, they have worse survival compared to never smoking patients. This has been observed clinically for decades, but then it is unknown how smoking leads to worsened AML survival. Smoking causes oxidative stress and altered DNA methylation that persists for decades in peripheral blood mononuclear cells, but these changes from smoking have not been evaluated in the context of AML. We hypothesize that smoking-induced molecular changes, including altered DNA methylation associated with poor AML prognosis, promote AML. We developed a novel model to …

Characterization Of 1,1-Diarylethylene Foxm1 Inhibitors Against High-Grade Serous Ovarian Carcinoma Cells, Cassie Liu

Theses & Dissertations

Forkhead box M1 (FOXM1) is a member of the conserved forkhead box (FOX) transcription factor family. Over the last two decades, FOXM1 has emerged as a multifunctional oncoprotein and a robust biomarker of poor prognosis in many human malignancies. FOXM1 and its associated oncogenic transcriptional signature are enriched in >85% of ovarian cancer cases, and FOXM1 expression and activity can be enhanced by a plethora of genomic, transcriptional, post-transcriptional, and post-translational mechanisms. As a master transcriptional regulator, FOXM1 promotes critical oncogenic phenotypes in ovarian cancer, including: (1) cell proliferation, (2) invasion and metastasis, (3) chemotherapy resistance, (4) cancer stem cell …

Sox2 Dosage Governs Tumor Cell Identity And Proliferation, Ethan P. Metz

Theses & Dissertations

The stem cell transcription factor SOX2 has been widely recognized for its critical roles during mammalian development. SOX2 expression has also been implicated in more than 20 types of human cancers. Importantly, the expression of SOX2 is regulated at multiple levels, which enables the tight regulation of SOX2 levels. Previous work from our laboratory has shown that elevating SOX2 from an inducible promoter inhibits the proliferation of several human tumor cell types. Other studies have reported that high levels of SOX2 are necessary to maintain lineage plasticity in advanced tumors. Thus, the dosage of SOX2 plays a critical role in …

Investigating The Impact Of Hypoxia On Reactive Oxygen Species Generation Within Murine Breast Cancer Cells, Jared Mcpeake

Biomedical Engineering Undergraduate Honors Theses

When cancer metastasizes from a primary tumor site to secondary site through the bloodstream or lymph, the cancer becomes more difficult to treat. For this reason, it is vital to study what indicates the metastatic potential of a tumor. Current research has shown that cell lines with high metastatic potential display increased levels of metabolic adaptability over their nonmetastatic counterparts after undergoing hypoxic conditions. One method of assessing this adaptability is to measure the concentration of reactive oxygen species (ROS) produced by the cells while undergoing oxidative stress. In highly adaptable metastatic cells, an increase of ROS buildup within the …

Novel Regulators Of Cellular Secretion Alter The Tumor Microenvironment To Drive Metastasis, Rakhee Bajaj

Dissertations and Theses (Open Access)

Lung cancer is a highly aggressive disease responsible for ~25% of all cancer-related deaths, due in part to its proclivity to metastasize. Treating metastasis holds potential for improving patient survival but requires a deeper investigation into the underlying mechanisms. Some of these processes that can regulate metastasis are: (1) Oncogenic targets of epithelial micro-RNAs (miRNAs) are epigenetically de-repressed upon loss of the miRNAs during epithelial-to-mesenchymal transition (EMT) and in cancer. EMT confers plasticity and fitness to cancer cells promoting their survival through the metastatic cascade. This cascade and EMT are initiated by loss of the miRNA200 family (miR-200) and the …

Characterization Of The Influence Of A Small Molecule Inhibitor On Ras-Related Proteins Interactions, Emilio Duverna

Graduate Theses and Dissertations

The Ras superfamily of small G proteins are involved in cell-signaling processes that, if not regulated, may lead to cell multiplication, apoptosis inhibition, and tumorigenesis. They function as molecular switches, which through GTP/GDP exchange cycle, switch on or off cellular activities. Overexpression and/or hyperactivity of these proteins have been linked to many diseases including various cancers. CDC42, a member of the Rho subfamily of the Ras superfamily of small G proteins, participates in the regulation of many cellular processes including cell adhesion, mitosis, and cytoskeletal rearrangements. CDC42 binds to and activates many effector proteins including CDC42-activated kinase (ACK). Abnormal activities …

Modulation Of Kras Structure And Dynamics By Kras Ubiquitination And Membrane Depolarization, Vinay Nair

Dissertations and Theses (Open Access)

KRAS, a 21 kDa small GTPase protein, functions as a molecular switch playing a key role in regulating cell proliferation. Dysregulation of KRAS signaling by oncogenic mutations leads to uncontrolled cell proliferation, a hallmark of cancer cells. Attempts to therapeutically target oncogenic KRAS have led to limited success resulting in a need to identify new mechanisms to targeting KRAS. The interaction of KRAS with its regulators, effectors, and the membrane present one such avenue. In this study, we investigated how post-translational covalent and environmental modifications could modulate these interactions of KRAS. Using computational molecular dynamics simulations, nuclear magnetic resonance spectroscopy …

The Effects Of Paclitaxel On Cellular Migration And The Cytoskeleton, Ashley Salguero-Gonzalez

Thinking Matters Symposium

In a clinical setting, some patients are exposed to an anti-cancer chemotherapy agent, paclitaxel. Cancerous cells undergo rapid, continuous cell division without control. Chemotherapy treatments try to slow and stop the uncontrollable cell division cycles and eliminate cancerous cells in the process. Paclitaxel serves as a treatment for some types of cancers, including lung, melanoma, bladder, and esophageal. Because it targets the cytoskeleton, paclitaxel can also influence cell migration. This project utilizes a cellular migration assay and an immunohistochemistry assay to analyze the effects of paclitaxel on the movement of cells and on the cytoskeleton of neuroglia rat cells with …

Utilization Of Bioinformatics And Immunocytochemistry To Examine Gap Junction Expression In Breast Cancers Cells, Jasmine D. Carter, Giovanni Reyes, Abeeha K. Choudhary, Eric A. Albrecht

Symposium of Student Scholars

Utilization of Bioinformatics and Immunocytochemistry to Examine Gap Junction Expression in Breast Cancers Cells.

Jasmine D. Carter¹, Giovanni Reyes¹, Abeeha Choudhary² and Eric A. Albrecht¹

Breast cancer is known for its diverse clinical classifications and expressing different levels of membrane proteins such as ion channels and gap junctions. This diversity allows more variations in cell polarization, which can lead to enhanced directional ion fluxes in certain breast cancer subtypes. We utilized the interactive web portal UALCAN to evaluate the gene expression data of gap junctions, ion exchange channels and cytoskeletal proteins in breast cancer …

Paratesticular Solitary Fibrous Tumour Mimicking Cellular Angiofibroma: An Unusual Morphology And Rare Site, Madiha Bilal Qureshi, Muhammad Usman, Qurratulain Chundriger, Nasir Uddin

Department of Pathology and Laboratory Medicine

Solitary fibrous tumour (SFT) is a ubiquitous benign mesenchymal tumour of fibroblastic origin, which occurs most often in middle-aged adults. It usually presents as lung mass originating from pleura, but extrapleural occurrence is also common. Tumour is characterised by hypo- and hyper-cellular areas of spindle-shaped cells, arranged in haphazard manner with dispersed staghorn-shaped vessels. Surgical excision is the curative treatment. SFTs of the primary testicular or paratesticular region are extremely rare, but they exhibit histologic findings similar to SFTs originating at other body sites. Here, we report the case of a paratesticular SFT in a 37-year male, who presented with …

Amphiphilic Cell-Penetrating Peptides Containing Natural And Unnatural Amino Acids As Drug Delivery Agents, David Salehi, Saghar Mozaffari, Khalid Zoghebi, Sandeep Lohan, Dindyal Mandal, Rakesh Tiwari, Keykavous Parang

Pharmacy Faculty Articles and Research

A series of cyclic peptides, [(DipR)(WR)₄], [(DipR)₂(WR)₃], [(DipR)₃(WR)₂], [(DipR)₄(WR)], and [DipR]₅, and their linear counterparts containing arginine (R) as positively charged residues and tryptophan (W) or diphenylalanine (Dip) as hydrophobic residues, were synthesized and evaluated for their molecular transporter efficiency. The in vitro cytotoxicity of the synthesized peptides was determined in human epithelial ovary adenocarcinoma cells (SK-OV-3), human lymphoblast peripheral blood cells (CCRF-CEM), human embryonic epithelial kidney healthy cells (HEK-293), human epithelial mammary gland adenocarcinoma cells (MDA-MB-468), pig epithelial kidney normal cells (LLC-PK1), and human epithelial …

Natural Phaeosphaeride A Derivatives Overcome Drug Resistance Of Tumor Cells And Modulate Signaling Pathways, Victoria Abzianidze, Natalia Moiseeva, Diana Suponina, Sofya Zakharenkova, Nadezhda Rogovskaya, Lidia Laletina, Alvin A. Holder, Denis Krivorotov, Alexander Bogachenkov, Alexander Garabadzhiu, Anton Ukolov, Vyacheslav Kosorukov

Chemistry & Biochemistry Faculty Publications

n the present study, natural phaeosphaeride A (PPA) derivatives are synthesized. Anti-tumor studies are carried out on the PC3, K562, HCT-116, THP-1, MCF-7, A549, NCI-H929, Jurkat, and RPMI8226 tumor cell lines, and on the human embryonic kidney (HEK293) cell line. All the compounds synthesized turned out to have better efficacy than PPA towards the tumor cell lines listed. Among them, three compounds exhibited an ability to overcome the drug resistance of tumor cells associated with the overexpression of the P-glycoprotein by modulating the work of this transporter. Luminex xMAP technology was used to assess the effect of five synthesized compounds …

Ultrasound 96 Probe Device Protocol For Cancer Cell Treatment, Aisling Field, Brijesh K. Tiwari, James F. Curtin, Julie R M Mondala, Janith Wanigasekara

Articles

Ultrasound is a sound wave with frequencies ranging between 20 kHz and 20 MHz. Ultrasound is able to temporarily and repeatedly open the BBB safely and enhance chemotherapeutic delivery without adverse effects. This novel technique in drug delivery benefits from the powerful ability of ultrasound to produce cavitation activity. Cavitation is the generation and activity of gas-filled bubbles in a medium exposed to ultrasound. As the pressure wave passes through the media, gas bubbles expand at low pressure and contract at high pressure. This leads to oscillation which produces a circulating fluid flow known as microstreaming around the bubble with …

Plasma Induced Reactive Oxygen Species-Dependent Cytotoxicity In Glioblastoma 3d Tumourspheres, Janith Wanigasekara, Carlos Barcia, Patrick J. Cullen, Brijesh Tiwari, James F. Curtin

Articles

The aim of this study was to determine the effects of a pin‐to‐plate cold atmospheric plasma (CAP) on U‐251 MG three‐dimensional (3D) glioblastoma spheroids under different conditions. 3D tumorspheres showed higher resistance to the CAP treatment compared to 2D monolayer cells. A single CAP treatment was able to induce cytotoxicity, while multiple CAP treatments augmented this effect. CAP was also able to induce cytotoxicity throughout the tumoursphere, and we identified that reactive oxygen species(ROS) plays a major role, while H2O2plays a partial role in CAP‐induced cytotoxicity in tumour-spheres. We conclude that ROS‐dependent cytotoxicity is induced uniformly throughout glioblastoma and epidermoid …

Inhibition Of De Novo And The Prion-Like Spread Of Amyloidogenesis Using In Vitro And In Vivo Disease Models, Johnson Anazoba Joseph

Electronic Theses and Dissertations

The aberrant fibrous, extracellular, and intracellular proteinaceous deposits in cells, organs and tissues are referred to as amyloids. These deposits are dominated by β-sheet structures that have been implicated in several neurodegenerative diseases and cancer. In this work, the types of amyloidosis studied include Parkinson’s disease (PD) using UA196 and NL5901 strains of Caenorhabditis elegans (C. elegans), Alzheimer’s disease (AD) using GMC101 strain of C. elegans, and cancer-associated mutant p53 aggregation in MIA PaCa-2 mutant cells. Several molecules including SK-129, NS132, NS163, bexarotene, a polyphenol (-)-epi-gallocatechine gallate (EGCG), ADH40, RD148, and RD242 were screened in vitro and in …