Cancer Biology Commons^™

Potential Role Of A Ruthenium-Based Compound Ru-Im In The Treatment Of Triple Negative Breast Cancer, Rachele Rameau

Dissertations, Theses, and Capstone Projects

Triple negative breast cancer (TNBC) is an aggressive and heterogeneous molecular subtype of breast cancer that has limited available treatments. The organometallic cationic ruthenium derivative Ru-IM was found to be highly water soluble, was differentially toxic for breast cancer cells and tumors, and was involved in the pI3K/AKT/mTOR pathway. However, a full understanding of genetic and epigenetic factors that can be part of regulatory mechanisms of Ru-IM is yet to be determined. Epigenetic assays including DNA methylation, histone acetylation and histone deacetylation were performed with the half inhibitory concentration (IC50) values of Ru-IM. Bisulfite sequencing of untreated and treated MDA-MB-231 …

Investigating The Role Of Early Growth Response 1 (Egr1) Gene In Riluzole-Induced Apoptosis In Osteosarcoma, Syeda Maryam Azeem

Dissertations, Theses, and Capstone Projects

Osteosarcoma is a rare but aggressive bone malignancy most commonly affecting adolescents and young adults (AYA). With 5-year survival rate stagnating over the last four decades despite the advancements in multi-modal therapy, drug repurposing offers a rapid path to new osteosarcoma treatments. Recent studies suggest that Riluzole, a drug approved for amyotrophic lateral sclerosis (ALS), may be repurposed for osteosarcoma treatment due to its ability to slow tumor progression and induce apoptosis. Previously, we have shown that Riluzole increases reactive oxygen species (ROS), activating c-Abl, which phosphorylates YAP in the nucleus. YAP then forms a complex with p73 to enhance …

Elucidating The Roles Of Eukaryotic Initiation Factors Involved In Dap5 Mediated Translation, Jacob Nk Quartey

Dissertations, Theses, and Capstone Projects

Translation initiation in eukaryotes is a highly regulated process essential for accurate protein synthesis. It is a dynamic process that involves a complex interplay between messenger RNAs (mRNAs), ribosomal subunits, and a host of initiation factors, ensuring precise start codon selection and the subsequent assembly of the translation machinery. This process has well been known to be mediated by the eukaryotic Initiation Factor (eIF4F), which consists of the cap binding protein eIF4E, the scaffolding protein eIF4GI, and the helicase factor eIF4A.The recognition and binding of eIF4E to the m⁷G cap structure of the mRNA is essential for the …

Understanding How Genetic Mutations Induce Oligodendrocyte Progenitors To Become Cancer Cells, Dennis Huang

Dissertations, Theses, and Capstone Projects

Gliomas are the most devastating adult brain tumors characterized by poor survival rate and limited options for treatment. Previous studies have shown that they are very heterogeneous and can be further sub-classified based on their transcriptional signature and the presence of specific mutations. One such subtype, is the “proneural glioma”, which is characterized by the enrichment in oligodendrocyte progenitor cell (OPC) transcripts and mutations in genes encoding for the tumor suppressor P53 (Trp53) and for Platelet Derived Grow Factor (PDGF) signaling. Since OPCs are the most abundant proliferative population in the adult brain, in this …

The Role Of Secondary And Tertiary Structure In The Cap-Independent Translation Of Fgf-9 And Hif-1-Alpha, Amanda Michelle Whittaker

Dissertations, Theses, and Capstone Projects

Under normoxic conditions, eukaryotes initiate translation of RNA through eIF4E recognition of the 5’ cap. However, under cellular stress, eukaryotic translation must be initiated through a 4E-independent, or “cap-independent” mechanism, involving eukaryotic initiation factor 4G (eIF4G) binding directly to the 5’ untranslated regions (5’ UTR) of the RNA. eIF4G binding then recruits the ribosome to the transcript. While this mechanism is useful for translation of apoptotic transcripts and transcripts involved in cell survival, cap-independent translation is also utilized by oncogenic RNA for tumorigenesis. Previous work by our lab and others has categorized this recruitment and initiation mechanism as either internal-ribosome-entry-site …

Regulation Of P21 Function By A Sense Long Non-Coding Rna Generated By Alternative Polyadenylation, Anthony Ramadei

Dissertations, Theses, and Capstone Projects

As cells are continually undergoing damage to the genome, a coordinated change in gene expression across thousands of genes is required for the progression of the DNA damage response (DDR). After initial sensing of DNA damage, the transcription factor p53 induces expression of target genes to halt the cell-cycle to allow DNA repair and induce either senescence or apoptosis. One of the p53 target genes is CDKN1A which encodes the cyclin dependent kinase inhibitor p21. p21 halts cell-cycle progression in response to DNA damage and can also induce senescence. However, p21 expression in cancer cells undergoing chemotherapy allows survival by …

High Mdmx (Mdm4) In Mutant P53 Expressing Breast Cancer Cells Activates The Cxcl12-Cxcr4 Metastasis Signaling Axis, Rusia H. Lee

Dissertations, Theses, and Capstone Projects

The metastasis-promoting G-protein coupled receptor (GPCR) CXCR4 is activated by the cytokine CXCL12 (also known as SDF-1) to promote metastasis through CXCR4 upregulation. High CXCR4-expressing cancer cells utilize CXCL12, the exclusive endogenous ligand of CXCR4, to intravasate into the blood as circulating tumor cells (CTCs) which then extravasate to distant metastatic sites. We previously determined the oncogenes, Mouse Double Minute 2 and 4 (MDM2 and MDM4, also known as MDMX), drive TNBC metastasis and positively correlate with high expression of CXCR4. Interestingly, this upregulation of CXCR4 was only observed in primary tumor cells grown in the tumor microenvironment …

Targeting Strategies To Optimize The Therapeutic Potential Of Gold Compounds Against Her2-Positive Breast Cancers, Afruja Ahad

Dissertations, Theses, and Capstone Projects

The overexpression of HER2 accounts for 20-30% of breast cancer tumors and not only serves as a marker for poor predictive clinical outcomes but also as a target for treatment. Antibody-drug conjugates (ADCs) combine the selectivity of monoclonal antibodies (mAbs) with the efficacy of chemotherapeutic drugs to provide targeted treatment without toxicity to normal tissue. Most of the ADCs currently in the clinic for cancer chemotherapy are based on complex organic molecules. In contrast, the conjugation of metallodrugs to mAbs has been overlooked when there is enormous potential in this area with the resurgence of metal-based drugs as prospective cancer …

Protein-Protein Interactions In Cell Cycle Proteins: An In Silico Investigation Of Two Important Players, Andriele Eichner

Dissertations, Theses, and Capstone Projects

The examination of the cell cycle carries significant implications for the biology, health, and overall existence of all living things. These implications span from the development and growth of these organisms to the aging process and cancer, as well as the potential of stem cell therapies to repair diseases and injuries. Numerous proteins of the cell cycle are essential for cellular division and proliferation and are widely conserved over the course of evolution. In this work, we aimed to investigate the molecular processes of protein-protein interactions in cell cycle proteins, centering on two key players: Cdc6 in budding yeast and …

Pre-Clinical Evaluation Of A Potential Ruthenium-Based Chemotherapeutic Agent For The Treatment Of Triple Negative Breast Cancer, Nazia Nayeem

Dissertations, Theses, and Capstone Projects

Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer that represents roughly 15% of all diagnosed breast cancers. TNBC is defined by the absence of expression of progesterone, estrogen, and human epidermal growth factor 2 receptors, and has a higher incidence rate in pre-menopausal women and women of African and of Hispanic ancestry. Due to the inability to target a receptor, treatment is limited to nonspecific chemotherapy or immunotherapy. Only one FDA approved therapy is available specifically to treat TNBC, which is antibody drug conjugate Sacitzumab-govitecan, given to patients who have already gone through two rounds of …

Multi-Target Ligand-Guided Selection (Ligs) Against B-Cell Specific Antigens Expressed In A Single Lymphoma Cell Population, Nicole B. Williams

Dissertations, Theses, and Capstone Projects

Nucleic acid ligands called aptamers are single-stranded DNA or RNA molecules which fold into functional three-dimensional structures to facilitate their target binding with high affinity and specificity. The method used to generate aptamers is an in vitro process called Systematic Evolution of Ligands by Exponential enrichment (SELEX). A variant of SELEX, cell-SELEX has been used to select aptamers against cell-surface proteins in their native state. We recently introduced a novel method called Ligand-Guided Selection (LIGS) to identify aptamers against cell-surface markers. Herein, we expanded LIGS method into a multiplexing platform to partition multiple aptamers against B-cell-specific antigens, CD19 and CD20, …

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 …

Study Of The Gain-Of-Function Mutant P53 And Parp1 In Triple-Negative Breast Cancer, Devon Lundine

Dissertations, Theses, and Capstone Projects

Cancer cells often lose expression of the p53 protein or express mutant forms of p53. Some of these mutant p53 proteins, called gain-of-function mutant p53, have gained oncogenic functions. Previously, our group observed mutant p53 R273H interacts with replicating DNA and upregulates the chromatin localization of several DNA replication factors including PCNA, MCM2-7, and PARP1 (termed the mtp53-PARP-MCM axis). In this thesis, we explore the contribution of mutant p53 and PARP1 in castration-resistant prostate cancer (mutant p53 P223L and V274F) and triple-negative breast cancer (mutant p53 R273H). In the castration-resistant prostate cancer cell line DU145, we examine two mutant p53 …

Synthesis, Characterization And Applications Of Peptide-Coated Nanoparticles, Mina Sadat Poursharifi

Dissertations, Theses, and Capstone Projects

Ovarian Cancer (OC) is the most lethal female malignancy worldwide, mainly due to its high recurrence rate and poor diagnosis. Most patients present with late stage of the disease, and less than 25% of patients survive the five years mark. Nanotherapy provides significant and unique benefits for drug efficacy, as nanoparticles (NPs) can increase the solubility, bioavailability, and permeability of many potent drugs. Poly(lactic-co-glycolic acid) (PLGA) is one of the most successful biodegradable polymers used in NPs formulations, mainly due to its biocompatibility and biodegradability. Polyethylene glycol (PEG) is one of the most commonly used moieties to prolong the NPs …

Anti-Cancer Effects By Interleukin 24, Xuelin Zhong

Dissertations, Theses, and Capstone Projects

Cancers develop as some cells acquire the ability, either by exogenous stimulation or by spontaneous mutation, to keep growing despite normal restraints. Up-regulating translation of oncogenes involved in cell proliferation and tumor development and down-regulating translation of tumor-suppressors that normally suppress tumor development are two most common mechanisms by which cancers develop. Therefore, it is crucial to study how these proteins get either up-regulated or down-regulated at translational level.

The eukaryotic translation initiation factor, which is composed of subunits such as eIF4A, eIF4G and eIF4E, is one of the key factors that contribute to efficient translation initiation. Interleukin 24 (IL-24), …

Cell Cycle Progression Effects Of Albumin, Sharmeen Uddin

Dissertations, Theses, and Capstone Projects

Progression through G₁ phase of the cell cycle is controlled largely by growth factors in early G₁ and by nutrients in late G₁ indicating sufficient raw material for cell division. We previously mapped a late G₁ cell cycle checkpoint for lipids upstream from a mammalian target of rapamycin complex 1 (mTORC1)-mediated checkpoint and downstream from a mid-G₁ checkpoint known as the Restriction point. We therefore investigated a role for lipids in progression through late G₁ into S-phase. Quiescent BJ-hTERT human fibroblasts primed back into G1 with FBS treatment, were treated with a mixture of …

Development Of Ligand Guided Selection (Ligs) To Identify Specific Dna Aptamers Against Cell Surface Proteins, Hasan Ekrem Zumrut

Dissertations, Theses, and Capstone Projects

Oligonucleotide aptamers (nucleic acid-based affinity reagents) are an emerging class of synthetic molecules that display high affinity and specificity towards their targets. Aptamer molecules for a target of interest are obtained using a combinatorial chemistry-based method termed systematic evolution of ligands by exponential enrichment (SELEX). SELEX is an in vitro selection process in which a random oligonucleotide library is subjected to repeated cycles of target incubation, separation, and amplification until target-specific evolved sequences become prevalent in the library. Typically, SELEX is used against target molecules such as small molecules and proteins, in their purified state. However, aptamers selected against purified …

Molecular Mechanisms Underlying Migratory And Immune-Evasion Properties Of Circulating Tumor Cells, Jeannette A. Huaman

Dissertations, Theses, and Capstone Projects

Metastasis is the leading cause of cancer deaths worldwide. However, there exist only limited treatment options and they are often ineffective. An important aspect of metastasis that requires study, but has previously been understudied is circulating tumor cells (CTCs). CTCs are a critical step in the metastatic cascade. They can be analyzed for the identification of key mechanisms in metastasis. To this end, we isolated CTCs from a syngeneic mouse model of hepatocellular carcinoma (HCC) and a human xenograft mouse model of castration-resistant prostate cancer (CRPC). From these mouse models, primary tumor and CTC lines were established. Functional characterization of …

Towards A Mathematical Model Of Motility Using Dictyostelium Discoideum: Proteins And Geometric Features That Regulate Bleb-Based Motility, Zully Santiago

Dissertations, Theses, and Capstone Projects

A variety of biological functions depend on actin organization. The organization of actin is tightly regulated by a plethora of extracellular and intracellular signaling, scaffolding, and actin-binding proteins. Dysfunctions in this regulation lead to immune diseases, increased susceptibility to pathogens, neurodegenerative diseases, developmental disorders, and cancer metastasis. A variety of actin-dependent processes, including cell motility, are regulated by several proteins of interest: Paxillin, a scaffolding protein; WASP, an actin nucleating protein; SCAR/WAVE, another WASP family actin nucleating protein; Talin, a cortex-to-membrane binding protein; Myosin II, an F-actin contracting motor protein; and Protein Kinase C, a protein kinase. D. discoideum cells …

Anti-Cancer Effects Of Oleocanthal And Extra Virgin Olive Oil, Limor Goren

Dissertations, Theses, and Capstone Projects

Oleocanthal is a phenolic compound found in varying concentrations in extra virgin olive oil. Oleocanthal has been shown to be active physiologically, benefiting several diseased states by conferring anti-inflammatory and neuroprotective benefits. Recently, we and other groups have demonstrated its specific and selective toxicity toward cancer cells; however, the mechanism leading to cancer cell death is still disputed. The current study demonstrates that oleocanthal induced damage to cancer cells’ lysosomes leading to cellular toxicity in vitro. Non-cancer cells were significantly less affected. Lysosomal membrane permeabilization following oleocanthal treatment in various cell lines was assayed via three complementary methods. Additionally, …

The Role And Regulation Of Alternative Polyadenylation In The Dna Damage Response, Michael R. Murphy

Dissertations, Theses, and Capstone Projects

Cellular homeostasis is achieved by the dynamic flux in gene expression. Post-transcriptional regulation of coding and non-coding RNA offers a fast method of adapting to a changing cellular environment, including deadenylation, microRNA (miRNA) pathway, and alternative polyadenylation (APA). In this dissertation, I explored some of the mechanisms involved in the post-transcriptional regulation of gene expression. The main hypothesis in these studies is that a single APA event after DNA damage is governed by specific conditions and factors outside of current known regulators of APA, and that the resultant transcript has a role in the DNA damage response (DDR). My aims …

Context Dependent Roles Of Mdmx (Mdm4) And Mdm2 In Breast Cancer Proliferation And Circulating Tumor Cells, Chong Gao

Dissertations, Theses, and Capstone Projects

Many human breast cancers overexpress the E3 ubiquitin ligase MDM2 and its homolog MDMX. Expression of MDM2 and MDMX occurs in both estrogen receptor α positive (ER+) and triple negative breast cancer (TNBC). We and others have reported that estrogen activated MDM2 strongly promotes proliferation in ER+ T47D breast cancer cells in a p53-independent manner. Whether MDM2 elicits in vivo p53-independent proliferative functions in T47D breast cancer cells has not been determined. Furthermore it has been shown that ectopic expression of MDM2 targets E-Cadherin for degradation thus leading to increased cell migration and invasion. Therefore we assessed the in vivo …

The Molecular Mechanisms Underlying The Cancer Killing Effect Of Interleukin-24, Leah Eshanie Persaud

Dissertations, Theses, and Capstone Projects

Interleukin-24 (IL-24) is an immunomodulatory cytokine that also displays specific anti-tumor effects across many cancer cell types. The tumor suppressor activities of IL-24 include inhibition of angiogenesis, metastasis, toxic autophagy, cancer-specific apoptosis, and sensitization to traditional cancer treatments like chemotherapy and radiation. Overexpression of IL-24 can selectively induce apoptosis in various cancer cells while having no adverse effects on normal cells. Due to this favorable killing effect, IL-24 is currently in phase II clinical trials. There is accumulating evidence that IL-24’s anti-cancer activity is primarily through the endoplasmic reticulum (ER) stress pathway but other pathways leading to cell death are …

An In Vitro And In Vivo Evaluation Of The Anticancer Potential Of Resveratrol And Pterostilbene Against Hpv-E6 Positive Cancers, Kaushiki Chatterjee

Dissertations, Theses, and Capstone Projects

Cervical cancer remains as one of the most prevalent cancers effecting women globally. Lack of awareness and affordable prophylactic and therapeutic options in developing countries drive the need for alternative low-cost approaches. Dietary polyphenols have gained increased attention as possible anti-cancer agents. Our study aims to investigate whether two natural structural analogs, resveratrol and pterostilbene, exhibit anti-HPV (Human papillomavirus) activity in cervical cancer. To determine the efficacy of these polyphenols, extensive in vitro and in vivo analyses were carried out. For the in vitro studies we utilized human HeLa cells (HPV18 positive) and murine TC1 cells (HPV 16 oncogene positive). …

Phospholipase D-Dependent Mtorc1 Activation By Glutamine, Elyssa Bernfeld

Dissertations, Theses, and Capstone Projects

Glutamine, the conditionally essential amino acid and most abundant amino acid in human sera, is a key nutrient required for sustaining cell proliferation. Glutamine is essential for nucleotide, protein, and lipid synthesis, all of which are essential for cell proliferation. The mammalian target of rapamycin complex 1 (mTORC1) is a highly conserved protein complex that acts as a sensor of nutrients, relaying signals for the shift from catabolic to anabolic metabolism. While glutamine plays an important role in activating mTORC1, the mechanism is not completely clear. Here we describe a Rag-independent mechanism of mTORC1 activation by glutamine that is dependent …

Strategies Involving The Food-Derived Agent Curcumin To Eliminate Brain Cancer, Sumit Mukherjee

Dissertations, Theses, and Capstone Projects

Glioblastoma (GBM) is one of the most deadly forms of cancer with a mean 5-year survival rate of ≤5%. We have used the non-invasive strategy of long-term intranasal (IN) delivery of a glioblastoma-directed adduct of curcumin (CC), CC-CD68Ab, into the brain of murine GBM cell line GL261-implanted mice to study the therapeutic effect of CC on GBM remission. The treatment caused GBM tumor remission in 50% of GL261-implanted GBM mice. A similar rescue rate (60%) was also achieved through long-term intraperitoneal (i.p) infusion of a highly bioavailable phosphotidylcholine (PC)-encapsulated formulation of CC, Curcumin Phytosome Meriva (CCP), into the GL261-implanted GBM …

Mechanisms For Survival And Drug Resistance In Cancer Cells, Matthew B. Utter

Dissertations, Theses, and Capstone Projects

PART I

Prostate cells are hormonally driven to grow and divide. Typical treatments for prostate cancer involve blocking the hormone androgen from activating the androgen receptor (AR) and thus inhibit growth and proliferation of the cancer. Androgen deprivation therapy (ADT) can lead to the selection of cancer cells that grow and divide independently of androgen receptor activation. Prostate cancer cells that are insensitive to androgens commonly display metastatic phenotypes and reduced long-term survival of patients. In this study, we provide evidence that androgen-insensitive prostate cancer cells have elevated phospholipase D (PLD) activity relative to the androgen-sensitive prostate cancer cells. PLD …

Anti-Proliferative Effects Of Garcinia Fruits In Breast Cancer Cells, Harini Anandhi Senthilkumar

Dissertations, Theses, and Capstone Projects

Breast cancer continues to be the second leading cause of death in women, even with the recent advances in research that has led to an improved understanding of molecular pathways and targets. Increasing mortality due to recurrence and lack of targeted drugs, especially in aggressive breast cancer subtypes such as triple negative breast cancer, has gained attention from the research community. With nearly 50% of the commonly used cancer drugs being sourced from plants, bioactive small molecules derived from a natural origin have immense potential as therapeutics. This study focuses on the anti-proliferative activities of benzophenones isolated from the edible …

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 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 …