Browsing by Author "Xelwa, Ntombikayise Hendrietta Marcia"

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Gene expression patterns of signalling pathways in PDAC: towards inhibiting metastases
(University of the Witwatersrand, Johannesburg, 2024) Xelwa, Ntombikayise Hendrietta Marcia
PDAC has a poor prognosis, with its prevalence varying by geographical location. In South Africa, PDAC ranked seventh among all cancer-related deaths in 2020 for both sexes. Specifically, it was the seventh leading cause of cancer death among males and the sixth among females. In 2020, an estimated 1,982 cancer deaths in South Africa were attributed to pancreatic cancer, with 1,006 occurring in males and 976 in females. However, the annual reported number of PDAC deaths in South Africa varies. This study aimed to identify potential novel therapeutic targets for PDAC in patients from the African population. Following ethical approval, tissue from fifteen patients (15 tumour and 15 corresponding normal tissues) were obtained during Whipple procedures from PDAC patients who consented to the study. Despite the development of new treatment strategies, patient outcomes have not significantly improved underscoring the necessity for extensive research to identify novel treatment options. A discovery study was conducted to determine the gene expression profile of signalling pathway-related genes using PDAC tissue samples. Top upregulated pathways included those involved in cytokine signalling, receptor kinase signalling, and PI3/Akt signalling. SPP1 was one of the most highly expressed genes identified in PDAC patients compared to normal corresponding tissues suggesting its potential role in the progression of the disease. To investigate SPP1's role in PDAC, RNA interference was employed to knockdown SPP1 in a PDAC cell line, MIA PaCa-2. Knockdown was confirmed by a significant reduction in SPP1 expression at the mRNA level. Combining SPP1 knockdown with conventional chemotherapy used for PDAC, gemcitabine, resulted in a synergistic effect, leading to an enhanced early apoptotic response. The study also examined the migratory and invasive capabilities of MIA PaCa-2 cells, revealing a noticeable decline in these abilities upon reduction in SPP1 expression with gemcitabine treatment. Furthermore, proteomic analyses uncovered the complex network of cellular processes influenced by the downregulation of SPP1 and the synergistic effects of combination therapy. Altogether, the findings from this study demonstrate the role of SPP1 in PDAC indicating that it could serve as a promising therapeutic target. The synergistic effects observed when SPP1 knockdown was combined with gemcitabine treatment suggest a potential avenue for developing more effective treatments for PDAC while exploring tumour cell adaptation for survival.
Molecular basis of metabolic reprogramming in innate immune cells: impact of drugs on the mitochondrial function
(2016) Xelwa, Ntombikayise Hendrietta Marcia
This study focused on reprogramming of energy metabolism of cancer cells, since most cancer and proliferating cells have been shown to display a metabolic shift by displaying increased dependence on glycolysis and reduced oxidative phosphorylation (OXPHOS) for energy. Dichloroacetate (DCA) and Methyl pyruvate (MP) were used to attempt the reversal of the metabolic program of THP-1 cells. Flow cytometry was used to determine the mode of cell death and to analyse the changes in cell cycle. In this study, an overexpression of TLR4 was observed in THP-1 cells treated with 5ng/ml of lipopolysaccharides (LPS). Further analysis of cell death showed that MP and DCA-treated cells resulted to minimal induction of apoptotic cell death. This suggests that the 2 drugs (MP and DCA) cause cell death via apoptosis. Furthermore, LPS treated cells (infected cancer cells) showed an increase in glycolysis (Warburg effect). This study has shown that indeed treatment with drugs such as MP and DCA was effective in reversing the glycolytic phenotype of THP-1 cells, resulting in cell death via apoptosis by boosting OXPHOS.