Cancer Biology Commons^™

Violacein Induces P44/42 Mitogen-Activated Protein Kinase‑Mediated Solid Tumor Cell Death And Inhibits Tumor Cell Migration, Toral Mehta, Koen Vercruysse, Terrance Johnson, Anthony Okechukwu Ejiofor, Elbert Myles, Quincy Antoine Quick

Biology Faculty Research

Microbial secondary metabolites have emerged as alternative novel drugs for the treatment of human cancers. Violacein, a purple pigment produced by Chromobacterium violaceum, was investigated in the present study for its anti‑tumor properties in tumor cell lines. Clinically applicable concentrations of violacein were demonstrated to inhibit the proliferative capacity of tumor cell lines according to a crystal violet proliferation assay. The underlying mechanism was the promotion of apoptotic cell death, as indicated by poly(ADP ribose) polymerase cleavage and p44/42 mitogen‑activated protein kinase signaling determined by western blot analysis. Collectively, this provided mechanistic evidence that violacein elicits extracellular-signal regulated kinase‑induced apoptosis …

Use And Misuse Of Material Transfer Agreements: Lessons In Proportionality From Research, Repositories, And Litigation, Tania M. Bubela, Jenilee Guebert, Amrita Mishra

Office of the Provost

Material transfer agreements exist to facilitate the exchange of materials and associated data between researchers as well as to protect the interests of the researchers and their institutions. But this dual mandate can be a source of frustration for researchers, creating administrative burdens and slowing down collaborations. We argue here that in most cases in pre-competitive research, a simple agreement would suffice; the more complex agreements and mechanisms for their negotiation should be reserved for cases where the risks posed to the institution and the potential commercial value of the research reagents is high.

Targeting Cell Cycle Proteins In Breast Cancer Cells With Sirna By Using Lipid-Substituted Polyethylenimines, Manoj Parmar, Hamidreza Montazeri Aliabadi, Parvin Mahdipoor, Cezary Kucharski, Robert Maranchuk, Judith C. Hugh, Hasan Uludag

Pharmacy Faculty Articles and Research

The cell cycle proteins are key regulators of cell cycle progression whose de-regulation is one of the causes of breast cancer. RNA interference (RNAi) is an endogenous mechanism to regulate gene expression and it could serve as the basis of regulating aberrant proteins including cell cycle proteins. Since the delivery of small interfering RNA (siRNA) is a main barrier for implementation of RNAi therapy, we explored the potential of a non-viral delivery system, 2.0 kDa polyethylenimines substituted with linoleic acid and caprylic acid, for this purpose. Using a library of siRNAs against cell cycle proteins, we identified cell division cycle …

Terahertz Imaging Platform To Characterize The Growth Of In-Vitro Breast Tumors, Scarlett-Marie Acklin

Inquiry: The University of Arkansas Undergraduate Research Journal

This study aimed at evaluating the ideal plating method and density for imaging with the terahertz (THz) spectrometer. In this study, different methods were used to grow in-vitro tumors using the 4T1 cell line. Here, attempts to grow breast tumors in-vitro were conducted. Results were produced in two environments, flat-bottomed plates and round-bottomed multiwell plates. The second method allowed for faster clumping and increased cell aggregation, producing tumors up to 7mm. Terahertz spectroscopy produced images that correlated well to photomicrographs taken of the in-vitro tumors. This methodology shows great promise for providing a reliable, parameter-controlled source of in-vitro breast tumors …

The Significance Of Crispr/Cas9-Directed Cul3 Knockout On Human Colorectal Cancer Cells, Zoe A. Lautz

Departmental Honors Projects

Cancer, the second leading cause of death in the US, is caused by mutations in select genes that alter cellular function leading to uncontrolled proliferation. Understanding the specific genes that drive cancer can lead to the generation of novel cancer therapies. To identify novel genes that drive cancer in the colon (CRC), lungs, and ovaries in mice, Starr et al. employed a transposon-based insertional mutagenesis system. One of the genes identified, APC, is mutated in 70-80% of human CRCs. CUL3, suspected to be a general driver gene, was discovered in the lung cancer screen. CUL3 was analyzed for its role …

Expression And Regulatory Effects On Cancer Cell Behavior Of Nell1 And Nell2 In Human Renal Cell Carcinoma, Ritsuko Nakamura, Takeru Oyama, Ryosuke Tajiri, Atsushi Mizokami, Mikiko Namiki, Masaru Nakamoto, Akishi Ooi

Biology Faculty Publications

Neural epidermal growth factor-like like (NELL) 1 and 2 constitute a family of multimeric and multimodular extracellular glycoproteins. Although the osteogenic effects of NELL1 and functions of NELL2 in neural development have been reported, their expression and functions in cancer are largely unknown. In this study, we examined expression of NELL1 and NELL2 in renal cell carcinoma (RCC) using clinical specimens and cell lines. We show that, whereas NELL1 and NELL2 proteins are strongly expressed in renal tubules in non-cancerous areas of RCC specimens, their expression is significantly downregulated in cancerous areas. Silencing of NELL1 and NELL2 mRNA expression was …

Pharmacologic Induction Of The Melanocotin 1 Receptor (Mc1r) Pathway Provides Protection Against Sunburn And Enhances Expression Of Antioxidant Enzymes In The Skin, Alexandra Amaro-Ortiz

Theses and Dissertations--Toxicology and Cancer Biology

The inability to tan properly after sun exposure strongly correlates with increased incidence of skin cancer. The melanocortin 1 receptor (MC1R) is a transmembrane Gs-coupled cell surface receptor found on epidermal melanocytes that transmits pro-survival and pro-differentiation signals mediated by the second messenger cAMP. Humans carrying loss-of-function polymorphisms in MC1R signaling exhibit higher incidences of skin cancers including melanoma.

This study focused on the physiologic effects of topical application of forskolin, an adenylate cyclase activator, in extension (Mc1r^e/e) K14-SCF animals, which model the fair-skinned UV-sensitive human. Twice daily application of the drug promoted accelerated pigmentation, increased skin darkening …

Effect Of Adjuvant And Neoadjuvant Anti-Telomerase With Anthracycline Based Chemotherapy On Triple Negative Breast Cancer Cells, Luke T. Pardy

Student Summer Scholars Manuscripts

Breast cancer is the second leading cause of cancer related death in women in the US. In addition, 20% of all breast cancer cases in the U.S. are from the subtype known as Triple-Negative Breast Cancer (TNBC), which is the most aggressive and invasive form of the disease. This type of breast cancer has the worst prognosis, a decreased survival rate, and no targeted therapy. Over the decades, interest in pre- (Neoadjuvant) and post- (Adjuvant) chemotherapy treatments, in the management of TNBC has increased. Therefore, we evaluated the Adjuvant and Neoadjuvant effects of anti-telomerases (BIBR 1532 and GV6) with anthracycline-based …

Pemetrexed, A Modulator Of Amp-Activated Kinase Signaling And An Inhibitor Of Wild Type And Mutant P53, Stuti Agarwal

Theses and Dissertations

New drug discoveries and new approaches towards diagnosis and treatment have improved cancer therapeutics remarkably. One of the most influential and effective discoveries in the field of cancer therapeutics was antimetabolites, such as the antifolates. The interest in antifolates increased as some of the antifolates showed responses in cancers, such as mesothelioma, leukemia, and breast cancers. When pemetrexed (PTX) was discovered, our laboratory had established that the primary mechanism of action of pemetrexed is to inhibit thymidylate 22 synthase (TS) (E. Taylor et al., 1992). Preclinical studies have shown that PTX has a broad range of antitumor activity in human …

Interaction Between Atm Kinase And P53 In Determining Glioma Radiosensitivity, Syed F. Ahmad

Theses and Dissertations

Glioblastoma multiforme (GBM) is the most common primary brain tumor. Studies have shown that targeting the DNA damage response can sensitize cancer cells to DNA damaging agents. Ataxia telangiectasia mutated (ATM) is involved in signaling DNA double strand breaks. Our group has previously shown that ATM inhibitors (ATMi) sensitize GBM cells and tumors to ionizing radiation. This effect is greater when the tumor suppressor p53 is mutated.

The goals of this work include validation of a new ATM inhibitor, AZ32, and elucidation of how ATMi and p53 status interact to promote cell death after radiation. We propose that ATMi and …

The Role Of Brct-Containing Proteins Brca1 And Paxip1 In Cancer, Ankita Jhuraney

USF Tampa Graduate Theses and Dissertations

Modular domains of proteins are important in cellular signaling processes. Eukaryotic cells are constantly undergoing DNA damage due to exogenous and endogenous sources of damage. The DNA damage response (DDR) involves a complex network of signaling events mediated by modular domains such as the BRCT (BRCA1 C-terminal) domains. Therefore, proteins containing BRCT domains are important for DNA damage detection and signaling. In this dissertation, we focus on two BRCT-containing proteins BRCA1 and PAXIP1. BRCA1 is a gene that is known to be associated with increased risk of hereditary breast and ovarian cancer. Germline variants of BRCA1 are assessed to determine …

Targeting T-Bet For Prevention Of Graft-Versus-Host Disease And Leukemia Relapse After Allogeneic Hematopoietic Stem Cell Transplantation, Jianing Fu

USF Tampa Graduate Theses and Dissertations

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective therapeutic option for many malignant diseases. However, the efficacy of allo-HSCT is limited by the occurrence of destructive graft-versus-host disease (GVHD). Since allogeneic T cells are the driving force in the development of GVHD, their activation, proliferation, and differentiation are key factors to understanding GVHD pathogenesis. On the other hand, antigen-presenting cells (APCs) are essential for allogeneic T-cell priming and the development of GVHD. The T-box transcription factor T-bet is a master regulator for IFN-γ production and Th1 differentiation. T-bet also regulates the functions of APCs including dendritic cells (DCs) and …

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

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 a heterotrimeric …

Lkb1 Deficient Non-Small Cell Lung Cancer Cells Are Vulnerable To Energy Stress Induced By Atp Depletion, Chao Yang

Dissertations and Theses (Open Access)

Lung cancer is the second most frequent cancer in United States, which represents about 13.5% of new cancer cases every year. It accounts for about 27.2% of all cancer related deaths, which is more than the sum of deaths caused by prancretic, breast and colorectal. On average, only about 16% of lung cancer patients survive beyond 5 years. LKB1 is the third most mutated gene in lung cancer. It has been shown that LKB1 is mutated in at least 15% to 30% of NSCLC. Tumor with LKB1 mutation is associated with poor differentiation, high metastasis and worse response to chemotherapy. …

Mdm2-Mediated Degradation Of Sirt6 Phosphorylated By Akt1 Promotes Tumorigenesis And Trastuzumab Resistance In Breast Cancer, Umadevi Thirumurthi

Dissertations and Theses (Open Access)

Sirtuin6 (SIRT6) is one of the members of the Sirtuin family and functions as a longevity assurance gene by promoting genomic stability. It also regulates various cancer-associated pathways and was recently established as a bonafide tumor suppressor in colon cancer. This suggests that SIRT6 is an attractive target for pharmacological activation in cancer treatment, and hence, identification of potential regulators of SIRT6 would be an important and critical contribution towards cancer treatment. Here, we show that AKT1 phosphorylates SIRT6 at Ser³³⁸ and induces MDM2-SIRT6 interaction, priming SIRT6 for degradation via the MDM2-dependent ubiquitin-proteasome pathway. Blocking SIRT6 Ser³³⁸ phosphorylation …

Novel Biomarkers Can Be Used As Targets To Combat Cancer, Harini Krishnan

Graduate School of Biomedical Sciences Theses and Dissertations

Cancer kills almost 8 million people per year worldwide. Therefore, about 13 people die from cancer every minute. Clearly, current cancer treatments are not completely effective. Moreover, many chemotherapeutic reagents are not very specific for cancer cells.

These agents attack rapidly dividing cells, including a wide array of normal cells, in addition to cancer cells, in the body. This lack of specificity can cause collateral damage and significant side effects in patients. More targeted therapies are needed to successfully combat cancer. Specific cancer biomarkers need to identified and characterized in order to develop better targeted anti-cancer drugs.

Tumor cells can …

Robust Meta-Analysis Shows That Glioma Transcriptional Subtyping Complements Traditional Approaches, Sanghoon Lee, Stephen Piccolo, Kristina Allen-Brady

Faculty Publications

Background Gliomas traditionally have been sub-classified
based on histopathological observations. However, this ap-
proach is subject to inter-observer variability, and histopatho-
logical features may not reflect the biological mechanisms that
drive tumor growth. High-throughput transcriptional profiling
has shown promise in objectively and reproducibly identify-
ing glioma subtypes. Most prior studies have typically used
only modest sample sizes and have sometimes overlooked
important data-processing steps to ensure sample quality and
to evaluate the robustness of quantitative findings. The pur-
pose of our study was to define robust glioma subtypes by
applying rigorous preprocessing and validation steps to 1,952
microarray samples aggregated …

Strategies To Sensitize Bladder Cancer Cells To Small Molecule Inhibitors Targeting The Pi3k Pathway, Giovanni Nitti

Dissertations and Theses (Open Access)

After many years of cancer research, it is well accepted by the scientific community that the future cure for this disease lies in a personalized therapeutic approach. Anticipating therapeutic outcome based on the genetic signature of a tumor has become the new paradigm. The PI3K pathway represents an ideal target for bladder cancer, as many of the key proteins of this pathway are altered or mutated in this particular type of cancer. Several small molecule inhibitors have been developed to target this pathway, but their efficacy has been shown to be heterogeneous among different cell lines and mostly cytostatic but …

Egfr Modulates Microrna Maturation In Response To Hypoxia Through Phosphorylation Of Argonaute2, Jia Shen

Dissertations and Theses (Open Access)

MicroRNAs (miRNAs) are generated by two-step processing to yield small RNAs that negatively regulate target gene expression at posttranscriptional level. Deregulation of miRNAs has been linked to diverse pathological processes, including cancer. Recent studies have also implicated miRNAs in regulatory roles to cope with a spectrum of stresses, such as hypoxia, which is frequently encountered in the poorly angiogenic core of a solid tumor. However, the upstream regulators of miRNA biogenesis machineries remain obscure, raising the question of how tumor cells efficiently coordinate and impose specificity on miRNA expression and function in response to stresses. Here, we show that EGFR, …

Brit1/Mcph1 Mediates The Dna Damage Response By Inducing P53 Stability And Promoting Atr Signaling, Edward Wang

Dissertations and Theses (Open Access)

The BRCT-repeat inhibitor of hTERT (BRIT1)/MCPH1 protein promotes the process of homologous recombination (HR) to repair DNA double strand breaks (DSBs). In response to DSBs, BRIT1 foci form at damaged sites, and recruits downstream repair proteins including 53BP1, MDC1, NBS1, and the SWI/SNF complex to the DSB region to promote DNA repair. BRIT1 copy number deficiency correlates with increased genomic instability in ovarian cancer specimens and breast cancer cell lines. Here, we propose that additional functions of BRIT1 include a direct interaction with the p53 tumor suppressor protein to promote p53 stability, and binding and recruitment of TopBP1 to sites …

Caspase-Dependent Signaling Underlies Glioblastoma Cell Death In Response To The Fungal Metabolite, Fusarochromanone, Elahe Mahdavian, Monique Marshall, Patrick M. Martin, Patrice Cagle, Brian A. Salvatore, Quincy A. Quick

Biology Faculty Research

Fungal metabolites continue to show promise as a viable class of anticancer agents. In the present study, we investigated the efficacy of the fungal metabolite, fusarochromanone (FC101), for its antitumor activities in glioblastomas, which have a median survival of less than two years and a poor clinical response to surgical resection, radiation therapy and chemotherapy. Using clinically applicable doses, we demonstrated that FC101 induced glioblastoma apoptotic cell death via caspase dependent signaling, as indicated by the cleavage of poly(ADP-ribose) polymerase, glioblastoma (PARP). FC101 also induced differential reactive oxygen species (ROS) levels in glioblastoma cells, contrasting a defined role of oxidative …

Defining The Sites Of Interaction Of The Fancd2, Fance, And Fancl Proteins, Joseph Mcclanaghan

Senior Honors Projects

Fanconi anemia (FA) is a rare genetic disease characterized by congenital defects, bone marrow failure and increased cancer susceptibility. FA is caused by mutations in any one of 16 genes. These genes encode for proteins that function in the FA-BRCA pathway to repair damaged DNA. Because of its important r­­­ole in DNA repair, this pathway is considered a major cellular tumor suppressor pathway, i.e. is critical for the prevention of cancer. Underscoring this fact, several of the FA genes - including BRCA2, BRIP1, PALB2, and RAD51C - are bona fide breast and ovarian cancer susceptibility genes.

My …

Phthalates And Phthalate Alternatives: Effects On Proliferative And Estrogenic Target Genes In Ishikawa Cells, Ranjani Sundar '15, Ping Yin, Serdar E. Bulun

Student Publications & Research

Phthalates are used as plasticizers in many of the products found in medical, household, and industrial applications. Much research has not been completed on the effects of these phthalates as potential endocrine disrupting chemicals (EDCs). As these chemicals are ingested, the mechanism by which they affect the reproductive system is largely unknown. The purpose of this study was to observe how 2 phthalates, Di-n-butyl phthalate (DBP) and Diisononyl phthalate (DINP), and 2 phthalate alternatives, Dioctyl terephthalate (DOTP) and BHT (butylated hydroxytoluene)affect uterine cells in comparison to a vehicle treatment and 17β-Estradiol treatment. Changes in expression of mRNA were observed using …

The Effect Of Small Molecule 390 On Cxcr4 Receptors, Selam B. Zenebe-Gete '14, Shruti R. Topudurti '14, Shum Andrew, Richard J. Miller

Student Publications & Research

CXCR4 is the chemokine receptor which aids in chemotaxis of stem cells, such as those in the bone marrow or the brain. SDF-1 is the natural ligand for the CXCR4 receptor. Similarities between novel molecule 390 synthesized by the Miller Lab and SDF-1 make this novel small molecule a possible agonist of the CXCR4 receptor. To determine whether 390 is an agonist to the CXCR4 receptor, we transfected cells with CXCR4 and exposed them to no agonist [vehicle control], SDF-1, or varying concentrations of our agonist drug. Next, we took calcium images using the dye fura-2, which indicates changes in …

Analysis Of The Regulation And Function Of Cip2a To Identify Candidate Biomarkers For Prostate Cancer, Diana Savoly

Graduate School of Biomedical Sciences Theses and Dissertations

Protein Phosphatase 2A (PP2A) is a tumor suppressor involved in the regulation of several signaling pathways and the cell cycle. PP2A becomes inactivated by several inhibitors, including Cancerous Inhibitor of PP2A (CIP2A). CIP2A has been identified as an oncogene, which is over-expressed in cancers and inhibits PP2A through direct interaction. CIP2A is recognized as a biomarker for cancer; however, it is not cancer-specific. Therefore, we identified and examined the use of CIP2A-regulated proteins as potential biomarkers in prostate cancer to better diagnose prostate cancer in patients. Currently, Prostate Specific Antigen (PSA) is widely used to detect prostate cancer; however, it …

Molecular Pap Biomarkers For Cervical Cancer Risk Assessment In Thinprep® Clinical Specimens, Jennifer Taylor

Graduate School of Biomedical Sciences Theses and Dissertations

Approximately 500,000 patients are diagnosed with cervical cancer worldwide each year, thus making it the second most common cause of cancer-related deaths in women. Persistent high-risk human papillomavirus (HR-HPV) infections induce cervical dysplasia by increasing the expression of two viral oncogenes, E6 and E7. Utilization of the Papanicolaous smear test (Pap test) has contributed to a decrease in morbidity and mortality of cervical cancer; however, subjective analysis of cell morphology with a limited amount of cells has led to a substantial rate of false positive and false negative diagnoses. A more objective and sensitive diagnostic tool for the detection of …

The Role Of Mammalian Cyclin C In Stress Response And Thyroid Disease Progression, Kun Wang

Graduate School of Biomedical Sciences Theses and Dissertations

The cellular response to stress involves changes in gene expression programs as well as the remodeling of subcellular organelles including the mitochondria. Important for this study, the mitochondria undergo extensive fragmentation when the cell is exposed to a variety of stressors. The cyclin C-Cdk8 kinase is a highly conserved transcription factor that associates with the RNA polymerase II holoenzyme. Using cyclin C knockout (CCNC^-/-) mouse embryonic fibroblast (MEF) cells, I revealed that cyclin C is required for the extensive mitochondrial fragmentation following treatment with pro-oxidants or the anti-cancer drug cisplatin. However, Cdk8 is not required for this process …

Clinical Features And Outcome Of Sporadic Colorectal Carcinoma In Young Patients: A Cross-Sectional Analysis From A Developing Country, Muhammad Nauman Zahir, Eisha Mahpara Azhar, Sobia Rafiq, Kulsoom Ghias, Munira Shabbir-Moosajee

Department of Biological & Biomedical Sciences

Background: Early onset colorectal carcinoma (CRC) is rare and has been hypothesized to be a biologically and clinically distinct entity personifying aggressive disease and worse survival.
Methods: Data for 131 patients was collected by retrospective chart review. Cox proportional hazard model was used to compute prevalence ratios and 95% confidence intervals.
Results: Early onset sporadic CRC accounted for 32% of all CRC treated in the specified time period. The mean age was 33.3 ± 7.9 years and the male to female ratio was 2 : 1. Colon and rectal cancers accounted for 55% and 45% of patients, respectively. 96% of …

Paracrine-Rescued Lobulogenesis In Chimeric Outgrowths Comprising Progesterone-Receptor-Null Mammary Epithelium And Redirected Wild-Type Testicular Cells, Robert D. Bruno, Corinne A. Boulanger, Sonia M. Rosenfield, Lisa H. Anderson, John P. Lydon, Gilbert H. Smith

School of Medical Diagnostics & Translational Sciences Publications

We have previously shown that non-mammary and tumorigenic cells can respond to the signals of the mammary niche and alter their cell fate to that of mammary epithelial progenitor cells. Here we tested the hypothesis that paracrine signals from mammary epithelial cells expressing progesterone receptor (PR) are dispensable for redirection of testicular cells, and that re-directed wild-type testicular-derived mammary cells can rescue lobulogenesis of PR-null mammary epithelium by paracrine signaling during pregnancy. We injected PR-null epithelial cells mixed with testicular cells from wild-type adult male mice into cleared fat-pads of recipient mice. The testicular cells were redirected in vivo to …

The Effect Of Lactic Acid On Mast Cell Function, Andrew J. Spence

Theses and Dissertations

This study shows for the first time the effect that L-(+)-lactic acid has on mast cell activation. Lactic acid is a byproduct of anaerobic glycolysis and is associated with inflammatory environments such as wounds, tumors and, asthma. In this study, pre-treatment with lactic acid altered cytokine production by bone marrow-derived mast cells (BMMC). Specifically, lactic acid enhanced cytokine secretion following IgE cross-linking, but decreased IL-33 mediated cytokine production. These effects were altered by genetic background, since C57BL/6 mast cells demonstrated the aforementioned result, but lactic acid had no effect on IgE-mediated cytokine production in 129/SvJ mast cells. The affected cytokines …