Cell and Developmental Biology Commons^™

Metabolic Dysregulation And Cancer Mortality In A National Cohort Of Blacks And Whites, Tomi Akinyemiju, Justin Xavier Moore, Suzanne Judd, Susan Lakoski, Michael Goodman, Monika M. Safford, Maria Pisu

Epidemiology and Environmental Health Faculty Publications

Background: We examined the association between metabolic dysregulation and cancer mortality in a prospective cohort of Black and White adults.

Methods: A total of 25,038 Black and White adults were included in the analysis. Metabolic dysregulation was defined in two ways: 1) using the joint harmonized criteria for metabolic syndrome (MetS) and 2) based on factor analysis of 15 variables characterizing metabolic dysregulation. We estimated hazards ratios (HRs) and 95% confidence intervals (CIs) for the association of MetS and metabolic dysregulation with cancer mortality during follow-up using Cox proportional hazards models.

Results: About 46% of Black and 39% of White …

Investigation Of Moringa Oleifera Leaf Extract And Its Cancer-Selective Antiproliferative Properties, Reagen H. Welch, Ashlee H. Tietje

Journal of the South Carolina Academy of Science

Moringa oleifera is a tree native to a number of Asian, African, and Central American countries and has been used in traditional medicine for an assortment of medicinal uses for centuries. Due to bioactive compounds within Moringa leaves, it is believed that Moringa leaf extract may possess cancer-selective antiproliferative properties. Previous research has been conducted in regards to this topic, but poor experimental design due to lack of necessary controls limits the legitimacy of anticancer claims. While previous research has shown that Moringa leaf extract has the potential to kill cancer cells, the research fails to demonstrate the effects of …

Tox Regulates Growth, Dna Repair, And Genomic Instability In T-Cell Acute Lymphoblastic Leukemia, Riadh Lobbardi, Jordan Pinder, Barbara Martinez-Pastor, Marina Theodorou, Jessica S. Blackburn, Brian J. Abraham, Yuka Namiki, Marc Mansour, Nouran S. Abdelfattah, Aleksey Molodtsov, Gabriela Alexe, Debra Toiber, Manon De Waard, Esha Jain, Myriam Boukhali, Mattia Lion, Deepak Bhere, Khalid Shah, Alejandro Gutierrez, Kimberly Stegmaier, Lewis B. Silverman, Ruslan I. Sadreyev, John M. Asara, Marjorie A. Oettinger, Wilhelm Haas, A. Thomas Look, Richard A. Young, Raul Mostoslavsky, Graham Dellaire, David M. Langenau

Molecular and Cellular Biochemistry Faculty Publications

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes. Using a transgenic screen in zebrafish, thymocyte selection–associated high mobility group box protein (TOX) was uncovered as a collaborating oncogenic driver that accelerated T-ALL onset by expanding the initiating pool of transformed clones and elevating genomic instability. TOX is highly expressed in a majority of human T-ALL and is required for proliferation and continued xenograft growth in mice. Using a wide array of functional analyses, we uncovered that TOX binds directly to KU70/80 and suppresses recruitment of this complex to DNA breaks to inhibit nonhomologous end joining (NHEJ) repair. …

Diverse Amide Analogs Of Sulindac For Cancer Treatment And Prevention, Bini Mathew, Judith V. Hobrath, Michele C. Connelly, R. Kiplin Guy, Robert C. Reynolds

Pharmaceutical Sciences Faculty Publications

Sulindac is a non-steroidal anti-inflammatory drug (NSAID) that has shown significant anticancer activity. Sulindac sulfide amide (1) possessing greatly reduced COX-related inhibition relative to sulindac displayed in vivoantitumor activity that was comparable to sulindac in a human colon tumorxenograft model. Inspired by these observations, a panel of diverse sulindac amide derivatives have been synthesized and their activity probed against three cancer cell lines (prostate, colon and breast). A neutral analog, compound 79 was identified with comparable potency relative to lead 1 and activity against a panel of lymphoblastic leukemia cell lines. Several new series also show good …

Role Of High Molecular Weight Hyaluronan In Ultraviolet B Light-Induced Transformation, Katelyn Cousteils

Electronic Thesis and Dissertation Repository

Keratinocyte carcinomas (KCs) are the most common cancers globally. Ultraviolet light is the key risk factor for these cancers but sunscreen has proven ineffective in their prevention, indicating a need for new prophylactic agents. Chronic elevation of high molecular weight (HMW) tissue hyaluronan (HA) in skin is linked to tumor resistance in the naked mole rat. To directly assess the role of this polysaccharide in resistance to keratinocyte tumors, a HMW HA phosphatidylethanolamine (HA-PE) formulation that penetrates skin and accumulates as coats around keratinocytes was prepared. The tumor resistance properties of the HA-PE formulation were tested in a mouse model …

Glycolytic Reprogramming Through Pck2 Regulates Tumor Initiation Of Prostate Cancer Cells, Jiangsha Zhao, Jieran Li, Teresa W.M. Fan, Steven X. Hou

Toxicology and Cancer Biology Faculty Publications

Tumor-initiating cells (TICs) play important roles in tumor progression and metastasis. Identifying the factors regulating TICs may open new avenues in cancer therapy. Here, we show that TIC-enriched prostate cancer cell clones use more glucose and secrete more lactate than TIC-low clones. We determined that elevated levels of phosphoenolpyruvate carboxykinase isoform 2 (PCK2) are critical for the metabolic switch and the maintenance of TICs in prostate cancer. Information from prostate cancer patient databases revealed that higher PCK2 levels correlated with more aggressive tumors and lower survival rates. PCK2 knockdown resulted in low TIC numbers, increased cytosolic acetyl-CoA and cellular protein …

Lim Protein Ajuba Directly Interacts With Replication Protein A To Prevent Atr Dna Damage Response, Sandy Wan Shan Fowler

Dissertations, Theses, and Capstone Projects

Integrity of the human genome is essential for viability and proliferation of human cells. Intrinsic (endogenous replication stress) or extrinsic (UV, chemotherapy drugs) agents threaten the stability of the genome by generation of single stranded (ss) DNA or double stranded (ds) DNA breaks. The DNA damage response (DDR) pathways are conserved in evolution and constitute systems that perform the surveillance, signaling, and repair of the damage in the nucleus. Unchecked and accumulation of DNA damage can lead to deleterious effects such as replication fork collapse, chromosome fusion and breakage. The dysregulations of DNA damage response pathways are hallmarks of tumorigenesis. …

The Glycosyltransferase Gnt-Iii Activates Notch Signaling And Drives Stem Cell Expansion To Promote The Growth And Invasion Of Ovarian Cancer, Heba Allam, Blake P. Johnson, Mao Zhang, Zhongpeng Lu, Martin J. Cannon, Karen L. Abbott

Articles

Glycosylation changes associated with cellular transformation can facilitate the growth and progression of tumors. Previously we discovered that the gene Mgat3 encoding the glycosyltransferase GnT-III is elevated in epithelial ovarian carcinomas (EOCs) and leads to the production of abnormal truncated N-linked glycan structures instead of the typical bisected forms. In this study, we are interested in discovering how these abnormal glycans impact the growth and progression of ovarian cancer. We have discovered using stable shRNA gene suppression that GnT-III expression controls the expansion of side-population cells, also known as cancer stem cells. More specifically, we found that GnT-III expression regulates …

The Role Of T-Box Proteins In Vertebrate Germ Layer Formation And Patterning, Sushma Teegala

Dissertations, Theses, and Capstone Projects

All of the tissues in triploblastic organisms, with the exception of the germ cells, arise from the three germ layers, ectoderm, mesoderm and the endoderm. The identification of the genes that underlie the differentiation of these layers is crucial to our understanding of development. T-box family proteins are DNA-binding transcriptional regulators that play important roles during germ layer formation in the early vertebrate embryo. Well-characterized members of this family, including the transcriptional activators Brachyury and VegT, are essential for the proper formation of mesoderm and endoderm, respectively. To date, T-box proteins have not been shown to play a role in …

Temporal Resolution Of Cell Death Signaling Events Induced By Cold Atmospheric Plasma And Electroporation In Human Cancer Cells, Danielle M. Krug, Prasoon K. Diwakar, Ahmed Hassanein

The Summer Undergraduate Research Fellowship (SURF) Symposium

Cancer treatment resistance and their invasive and expensive nature is propelling research towards developing alternate approaches to eradicate cancer in patients. Non-thermal, i.e., cold atmospheric plasma (CAP) and electroporation (EP) applied to the surface of cancerous tissue are new methods that are minimally invasive, safe, and selective. These approaches, both independently and synergistically, have been shown to deplete cancer cell populations, but the signaling mechanisms of death and their timelines of action are still widely unknown. To better understand the timeframe of signaling events occurring upon treatment, human cancer cell lines were treated with CAP, EP, and combined CAP with …

Rna Sequencing In The Development Of Cancer-Cachexia, Thomas Allen Blackwell

Graduate Theses and Dissertations

Introduction: Cancer is a major public health problem in the U.S. and the world. In 2013 there were an estimated 1,660,290 new cases of cancer in the U.S. Cancer-Cachexia (CC) is a common effect of many cancers, and is directly responsible for 20-40% of cancer-related deaths. The mechanisms that control the development of CC are not well understood. Most investigations of CC focus on the post-cachectic state and do not examine the progression of the condition. The purpose of this study was to utilize RNA sequencing to analyze transcriptomic alterations throughout the progression of CC. Methods: Lewis Lung Carcinoma cells …

Histone Deacetylase Inhibition Induces Apoptosis And Cell Cycle Dysregulation In Human And Murine Cancer Cell Lines, Joseph Skurski

Theses and Dissertations

Carcinogenesis is a complex multistep process that requires tumor cells to grow rapidly while overcoming growth inhibitory signals and sustained challenges from the host immune response. Mutations within promoter or enhancer regions, along with epigenetic changes, can induce aberrant expression of genes that regulate differentiation, cell cycle, and apoptosis, all of which enhance potential for cellular transformation. In recent years, our understanding of the biological processes that influence the activation and repression of transcription have evolved to highlight the role of chromatin architecture, and how chromatin remodeling may be utilized for the potential therapeutic benefit of genetic disease. Histone deacetylase …

Basigin-2 Mediated Activation Of Erk1/2 Signaling In Human Glioblastoma Multiforme Cells, Erik R. Peterson

All NMU Master's Theses

Glioblastoma multiforme (GBM) is the most common malignant form of human brain cancer. GBM tumor cells overexpress the protein Basigin (Bsg) at the cell surface where it contributes to malignancy via stimulation of matrix metalloproteinase (MMP) expression in surrounding normal tissues, resulting in the degradation of the extracellular matrix (ECM) surrounding tumors, promoting remodeling of the tumor borders, stimulating growth. In work by Belton et al. (2008), human uterine endometrial cells treated with a recombinant form of human basigin possessing the extracellular domain of the Bsg protein (rBsg-ECD) showed activation of the Mitogen-Activated Protein Kinase (MAPK) signaling pathway proteins, ERK1/2. …

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 …

Investigating The Synergistic Effects Of Cisplatin And Two Curcuminoid Compounds On Cancer, Denis Hodzic

Mahurin Honors College Capstone Experience/Thesis Projects

Cisplatin is an anti-cancer drug effective against several cancers which can produce the serious side-effect of hearing loss. Curcumin, a natural plant compound, can increase the activity of cisplatin against cancer and counteract cisplatin’s effect against hearing. Because curcumin exhibits poor bioavailability, there is considerable interest in developing synthetic curcumin analogs (curcuminoids) that are more soluble and which retain anti-cancer activity and otoprotective function. This study investigated whether two curcuminoids, EF-24 and CLEFMA, increase the cytotoxic and ototoxic effects of cisplatin against the lung cancer cell line, A549, and the colorectal cancer cell line, Caco2. Cytotoxicity was measured by using …

Exploring Cancer Metabolism Using Stable Isotope-Resolved Metabolomics (Sirm), Ronald C. Bruntz, Andrew N. Lane, Richard M. Higashi, Teresa W. -M. Fan

Center for Environmental and Systems Biochemistry Faculty Publications

Metabolic reprogramming is a hallmark of cancer. The changes in metabolism are adaptive to permit proliferation, survival, and eventually metastasis in a harsh environment. Stable isotope-resolved metabolomics (SIRM) is an approach that uses advanced approaches of NMR and mass spectrometry to analyze the fate of individual atoms from stable isotope-enriched precursors to products to deduce metabolic pathways and networks. The approach can be applied to a wide range of biological systems, including human subjects. This review focuses on the applications of SIRM to cancer metabolism and its use in understanding drug actions.

Mitochondrial Dynamics Controls T Cell Fate Through Metabolic Programming, Michael Buck

Arts & Sciences Electronic Theses and Dissertations

Activated effector T (TE) cells augment anabolic pathways of metabolism, such as aerobic glycolysis, while memory T (TM) cells engage catabolic pathways, like fatty acid oxidation (FAO). However, signals that drive these differences remain unclear. Mitochondria are metabolic organelles that actively transform their ultrastructure. Therefore, we questioned whether mitochondrial dynamics controls T cell metabolism. We show that TE cells have punctate mitochondria, while TM cells maintain fused networks. The fusion protein Opa1 is required for TM, but not TE cells after infection, and enforcing fusion in TE cells imposes TM cell characteristics and enhances antitumor function. Our data suggest that, …

Cancer As A Metabolic Disease, Javaria Haseeb

Honors Senior Capstone Projects

Despite decades of intensive scientific and medical efforts to develop efficient and effective treatments for cancer, it remains one of the prime causes of death today. For example, in 2016, there will be an estimated 1,685,210 new cases of cancer and 595,690 deaths due to cancer in the United States alone (National Cancer Institute). Worldwide in 2012, there were an estimated 14 million new cases of cancer and 8.2 million deaths due to cancer. In order to come up with better methods of detection and more successful modes of treatment, it is crucial that scientists understand the depth of not …

A Machine Learning Classifier Trained On Cancer Transcriptomes Detects Nf1 Inactivation Signal In Glioblastoma, Gregory P. Way, Robert J. Allaway, Stephanie J. J. Bouley, Camilo E. Fadul, Yolanda Sanchez, Casey Greene

Dartmouth Scholarship

We have identified molecules that exhibit synthetic lethality in cells with loss of the neurofibromin 1 (NF1) tumor suppressor gene. However, recognizing tumors that have inactivation of the NF1 tumor suppressor function is challenging because the loss may occur via mechanisms that do not involve mutation of the genomic locus. Degradation of the NF1 protein, independent of NF1 mutation status, phenocopies inactivating mutations to drive tumors in human glioma cell lines. NF1 inactivation may alter the transcriptional landscape of a tumor and allow a machine learning classifier to detect which tumors will benefit from synthetic lethal molecules. We …

Investigating The Essential Roles Of Dprl-1 In Drosophila Melanogaster, Alex Lee

Summer Research

Phosphatase of Regenerating Liver (PRL) proteins regulate a number of important cellular processes, including cell growth and division. Humans have three PRL proteins: PRL-1, PRL-2, and PRL-3. An accumulation of evidence has shown that elevated levels of PRLs are strongly correlated with uncontrollable growth and metastasis of tumors. However, contradictory findings have arisen indicating that PRLs instead function to halt cell division thereby preventing uncontrollable tumor growth. In light of these results, the underlying mechanisms regarding how PRLs function within cellular processes remains unclear. To investigate the functions of PRLs, we will create transgenic fruit flies (Drosophila melanogaster) …

The Effect Of K562-Il21-2 Plasma Membrane Particles On The Proliferation Of Natural Killer Cells To Fight Cancer, Michelle Prophete

Honors Undergraduate Theses

Immunotherapy has emerged as a current and future paradigm of cancer treatment, which utilizes the body’s immune system to eradicate cancer. Natural Killer (NK) cells as part of the innate immune system have immense potential in their anti-tumor cytotoxic activities and host cell surveillance properties. NK cells comprise approximately five to fifteen percent of peripheral blood lymphocytes and can be proliferated in vitro using recently developed methods with co-cultures with feeder cells (derived from engineered tumor cells) or plasma membrane (PM) particles, produced from the fore mentioned feeder cells, in combination with soluble cytokines. For efficient growth and maintenance of …

The E. Coli Protein Ybgl: A Novel Dna Repair Enzyme?, Mason H. Conen, Brooke D. Martin, Kent Sugden, Savannah Whitfield

Undergraduate Theses, Professional Papers, and Capstone Artifacts

Cr(V) is a carcinogen that oxidizes guanine aggressively to form spiroiminodihydantion (Sp) and guanidinohydantoin (Gh), both of which contain an unusual hydantoin moiety that cause G→T transversion mutations at a high rate. Endonuclease VIII (nei) can recognize and excise these oxidation products from DNA and is translated as one of five protein products of the Nei operon in Escherichia coli (E. coli). However, the functions of the other four proteins remain unknown. To address this gap in knowledge, we focused on one of the four that immediately precedes nei, the ybgL protein. Previous work by our group has suggested a …

Understanding The Genotoxicity Of Silver Nanoparticles And The Chemoprevention Of Pomegranate Extract, Sameera Nallanthighal

Legacy Theses & Dissertations (2009 - 2024)

The use of silver nanoparticles (AgNPs) in a wide variety of consumer products (i.e. toothpastes, food containers, dietary supplements and garments) for their antimicrobial properties can lead to potential oral exposure in humans. To enhance their stability, AgNPs are coated with capping agents such as citrate and polyvinylpyrrolidone (PVP). Despite the lack of significant general toxicity based on hematology, blood chemistry and histology evaluations, the potential genotoxic effects of AgNPs cannot be ruled out and have to be addressed. Studies examining the genotoxic risks of AgNPs are needed because genotoxicity is a strong indicator of cancer risk. Here we examined …

The Role Of Progesterone Receptor Membrane Component 1 In Receptor Trafficking And Disease, Kaia K. Hampton

Theses and Dissertations--Pharmacology and Nutritional Sciences

The progesterone receptor membrane component 1 (PGRMC1) is a multifunctional protein with a heme-binding domain that promotes cellular signaling via receptor trafficking, and is essential for some elements of tumor growth and metastasis. PGRMC1 is upregulated in breast, colon, lung and thyroid tumors. We expanded the analysis of PGRMC1 in the clinical setting, and report the first analysis of PGRMC1 in human oral cavity and ovarian tumors and found PGRMC1 to correlate with lung and ovarian cancer patient survival. Furthermore, we discovered a specific role for PGRMC1 in cancer stem cell viability. PGRMC1 directly associates with the epidermal growth factor …

Thyroid Hormone Receptor Ss (Trß) Regulation Of Runt-Related Transcription Factor 2 (Runx2) In Thyroid Tumorigenesis: Determination Of The Trß Nuclear Protein Complexes That Associate With The Runx2 Gene., Thomas Howland Taber

Graduate College Dissertations and Theses

Thyroid Tumorigenesis is typically a well understood process, with well delineated oncogenic factors. Follicular and papillary thyroid cancers are typically survivable, with 5-year survival rates being >95% for Stage I-III of both cancer types. Anaplastic thyroid cancer, in contrast, lacks this prognosis, and is the most lethal of all endocrine-related cancers. The median survival time after a diagnosis is generally between 6-8 months, with a 5-year survival rate of <10%. Current treatment for anaplastic thyroid cancers routinely meet roadblocks, as resistance is quickly developed. Even non-discriminatory kinase inactivators, such as sorafenib, which are generally considered a drug of last resort, are unable to effect survival rates. As such, there is a clear need for further investigation of the causes of anaplastic thyroid cancer mechanisms.

Previous work in the Carr lab revealed a novel regulatory pathway of an oncogene that is associated with several other endocrine-related cancers, as well as other non-endocrine-related cancers. Specifically, the Runt-related …