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Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.
The full abstract for this thesis is available in the body of the thesis, and will be available when the embargo expires.
Prostate cancer (PCa) is among the most commonly-occurring cancers worldwide and a leading cause of cancer-related deaths in men. Local non-invasive PCa is highly treatable but limited treatment options exist for those with locally-advanced and metastatic forms of the disease. This underscores the need to identify mechanisms mediating PCa progression. One well-established driver of PCa progression is the androgen receptor protein whose transcriptional targets include genes related to cell growth and cell cycle progression. Consequently, the androgen receptor axis is the target of many therapies for those with PCa. Another important aspect of disease progression relates to cancer spread or metastasis. Epithelial-to-mesenchymal transition (EMT) is a cellular process executed during embryogenesis and is defined as the transition of cells from an epithelial phenotype to a mesenchymal phenotype. It is suspected that metastasis is, in part, due to inadvertent re-activation of EMT. Another theorized cause of cancer progression is due to the existence of tumour-initiating cells or ‘cancer stem cells’ which resist conventional radiation- and chemotherapies and seed relapse and metastasis.The semaphorins are a large grouping of membrane-associated or s¬ecreted signalling proteins whose normal roles reside in embryogenesis and neuronal development. During these processes the semaphorins establish chemotactic gradients and direct cell movement. Various semaphorin family members have been found to be up- or downregulated in a number of cancers. One family member, semaphorin 3C (SEMA3C), has been implicated in several types of cancer and its increased expression is correlated with PCa stage. Given SEMA3C’s roles in development and its augmented expression in PCa, we hypothesized that SEMA3C promotes cancer progression by driving EMT and stem-like characteristics. In the present study, we show that SEMA3C is a direct transcriptional target of the androgen receptor and further show that ectopic expression of SEMA3C in RWPE-1, a normal prostate epithelial cell line, leads to an upregulation of EMT and stem markers which is accompanied by acquisition of invasiveness and stem-like phenotypes. The broader impact of this work pertains to the clinical implications of SEMA3C’s involvement in PCa and linking SEMA3C and AR to metastatic recurrent PCa.
Cutaneous melanoma is a life-threatening skin cancer due to its poorly understood invasivnature and high metastatic potential. On the other hand, translational dysregulation has been shown to have an important role in the development and progression of cancer. In this study we investigated the role of two translational factors called eukaryotic translation initiation factor 5A2 (EIF5A2) and eukaryotic translation initiation factor 4E (eIF4E) in melanoma. Using tissue microarray (TMA) we showed that eIF4E expression and nuclear and cytoplasmic EIF5A2 expression increased from dysplastic nevi to primary melanomas, and further increased in metastatic melanomas. The expression of eIF4E and both EIF5A2 forms were correlated with melanoma thickness and AJCC stages and were inversely correlated with the 5-year survival of melanoma patients. TMA data also revealed that nuclear EIF5A2, cytoplasmic EIF5A2 and eIF4E expression were all directly correlated with MMP-2 expression which is an important factor for promoting cancer cell invasion. In addition, in vitro analysis revealed that both melanoma cell invasion and MMP-2 activity decreased as a result of EIF5A2 or eIF4E knockdown indicating that EIF5A2 and eIF4E may be responsible for increasing melanoma cellinvasiveness at least partly through increasing MMP-2 activity. Our experiments also showed that EIF5A2 is a novel downstream target of p-Akt. Additionally, we indicated that both EIF5A2 and eIF4E may play a role in EMT by upregulating mesenchymal markers and downregulating epithelial markers. eIF4E knockdown also decreased cell proliferation and increased apoptosis and caused a decrease in c-myc and BCL-2 expression, and an increase in cleaved PARP and cleaved caspase-3 expression and chemosensitivity. Nuclear and cytoplasmic EIF5A2 expression were found to be significantly correlated, and simultaneous expression of both was significantly associated with poor overall and disease-specific 5-year survival of melanoma patients. This correlation; however, was not perfect which may indicate the differential regulation of nuclear and cytoplasmic EIF5A2 expression in melanoma. Multivariate Cox regression analysis revealed that eIF4E expression, nuclear and cytoplasmic EIF5A2 expression and the combination of the last two were an adverse independent prognostic factor for melanoma patients. Therefore, they have the potential to be used as prognostic therapeutic markers in melanoma.
Cutaneous melanoma remains to be not only one of the most deadly among all skin cancers, but it’s one of the most deadly of all cancers in general. It is crucial to have an early detection of the disease despite lacking any effective treating options while therapeutic strategies of later stages of melanoma have yet to be discovered. Meanwhile, the mechanism modulating the progression of melanoma is still not well understood. In this study, we investigated KAI1’s role during metastasis regulation in human melanoma. We proposed the tumor suppressor function of KAI1 was directly correlated with KAI1 expression and showed the loss of KAI1 expression in melanoma patient samples significantly correlated with poorer patient survival. Furthermore, forced KAI1 expression was shown to suppress melanoma cell migration and invasion primarily through its regulation of another tumor suppressor gene: inhibitor of growth 4 (ING4). Moreover, KAI1 expression significantly suppressed melanoma angiogenesis by reducing HUVEC cell growth and tubular structure formation. In fact, KAI1’s regulation on angiogenesis was associated with the modulation of IL-6 and VEGF expression. Additionally, we investigated the mechanistic pathway between KAI1 and ING4 and found that KAI1 suppressed Akt phosphorylation through the regulation of EGFR and VEGFR phosphorylation. Meanwhile, the semaphorin 3C (SEMA3C) protein had been identified as an oncogene that induced cancer cell migration and invasion. In this study, we found that SEMA3C was also able to induce melanoma angiogenesis observed in the elevated HUVEC growth and tube formation. Furthermore, we showed that KAI1 expression suppressed SEMA3C-induced melanoma angiogenesis whereas KAI1 knockdown rescued the SEAM3C-suppressed melanoma angiogenesis. According to our study, we have illustrated a regulatory pathway of KAI1 on the regulation of melanoma metastasis which involves the regulation of the PI3K/Akt pathway and the tumor suppressor gene ING4. Also, the restoration of KAI1 expression was shown to significantly suppress melanoma cancer cell migration, invasion and angiogenesis. Taken together, KAI1 was a potential diagnostic marker for advanced melanoma and the restoration of KAI1 expression might shed light on new therapeutic approaches for treating cutaneous human melanoma.
No abstract available.
Master's Student Supervision
Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.
Excessive or dysregulated immune responses require clinical intervention to preventtissue damage and organ dysfunction. Unfortunately, many of these clinical interventions haveundesired side effects; therefore, development of novel therapeutic agents with differentmechanisms of action would be immensely beneficial. Mounting evidence in in vitro and in vivostudies implicate amino acid deprivation (AAD) as a key natural mechanism by which the bodyregulates immune responses and suppresses immune cell activation and function. However, therole of aminoacyl-tRNA synthetase (aaRS) inhibitors in regulating immune responses is largelyunknown. Since inhibitors of aaRSs limit the cell’s availability to specific amino acids andthereby creating an amino acid limiting environment, a deeper investigation of aaRS inhibitorinducedamino acid deprivation and its ability to regulate immune cell function is needed. Wehypothesized that aminoacyl tRNA synthetase inhibitors might represent a novel class ofimmunosuppressive and/or anti-inflammatory agents that act as pharmacomimetics of aminoacid deprivation.Two specific aims were accomplished in this study. We first showed that borrelidin is apotent inhibitor of T-cell proliferation, activation and cytokine production. As compared withother primary cells and cell lines, we determined borrelidin is most effective at suppressing Tcells.We then showed borrelidin potently suppresses lipopolysaccharide (LPS) induced- releaseof inflammatory cytokines such as TNF alpha (TNFα) from primary splenocytes andsuppression of TNFα occurs at the level of protein synthesis. In both T-cells and macrophages,intracellular staining and flow cytometry identified that borrelidin promotes activation of thegeneral control non-derepressible 2 (GCN2) stress response pathway and inhibition of themammalian target of rapamycin (mTOR) pathway. iiiThe findings presented in this thesis collectively demonstrate that borrelidin is a potent immunosuppressive and anti-inflammatory agent. These findings help us to better understand the role of aminoacyl-tRNA synthetase inhibitors in regulating immune function.
The phosphatidylinositol 3-kinase (PI3K) signaling pathway is a critical regulator of cell physiology. This project aims to investigate several novel approaches to target the PI3K pathway. First, in order to determine the importance of PI3K regulators on normal cells, I investigated the effect of PTEN haploinsufficiency on glucose regulation in mice. Even a 50% reduction in PTEN expression was sufficient to increase phosphorylation of the downstream targets AKT and GSK3β.Next, I wanted to see if PI3K pathway could treat idiopathic thrombocytopenic purpura (ITP). Since the established ITP therapy (IVIg) is thought to signal through SH2-containing inositol 5’ phosphatase (SHIP), I tested the ability of a SHIP activator AQX-MN100 to reverse a murine model of ITP. In the classic model of ITP, AQX-MN100 was unable to rescue mice from antibody-mediated platelet destruction. However, prophylactic AQX-MN100 prevented the infection-mediated form of ITP.I then studied the potential uses of AQX-016A/AQX-MN100 in the hematopoietic malignancies multiple myeloma (MM) and mantle cell lymphoma (MCL). AQX-016A/AQX-MN100 successfully induced apoptosis of the cancer cell lines in vitro in both a time and dose dependant manner.I then investigated the potential of a small molecule ILK inhibitor to inhibit early prostatic dysplasia/hyperplasia in a murine model. Under the initial experimental parameters chosen, the ILK inhibitor was not able to inhibit dysplasia/hyperplasia. However, further studies are required to determine whether ILK inhibition may be an effective therapeutic strategy for treatment of prostate cancer.Finally, I attempted to potentiate the effects of PI3K pathway inhibitors with borrelidin, an inhibitor of tRNA synthetase, which successfully exhibited synergy with the PI3K inhibitor LY294002, but only exhibited additive effects with the ILK inhibitor. The results of this project show the validity of targeting members of the PI3K pathway either in alone or in combination with a synergistic pathway.
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