[Truncated abstract] The enlargement of the heart, also known as myocardial hypertrophy, is thought to be a compensatory process that maintains the mechanical function of the heart in response to stress factors such as pressure or volume overload. Although this process is initially compensatory, it frequently results in heart failure and death. Cardiac hypertrophy is a complex process involving changes in the individual cardiac muscle cells, cardiac myocytes. As well as the morphological changes that result from hypertrophy, there are molecular changes within each cell that regulate the hypertrophic process. These molecular changes involve many different pathways within the cardiac myocytes and remain poorly understood . . . Both STAT3α and β overexpression resulted in the upregulation of the VEGF, MnSOD and SOCS-3 genes. This indicates that in the heart, STAT3β is able to activate the gene expression of these genes in a similar manner to STAT3α. However, STAT3α or β activation alone is not enough to induce cardiac hypertrophy. In conclusion, the results presented in this thesis determined a novel role for ERK in the induction of cell death in the heart and revealed many changes in cardiac gene expression following ERK activation. These genes may be the mediators of ERK responses and their identification provides valuable information and direction for further research in this area. One consequence of ERK activation was the negative regulation of the STAT3 pathway. Further investigation revealed for the first time that the STAT3 proteins themselves may not be involved in the induction of cardiac hypertrophy and that STAT3β, initially thought to be a transcriptional repressor, can induce the expression of genes that are known to be activated by STAT3α in the heart. Therefore, these results help to better understand the roles of these two signalling pathways in the heart.

Indiana University-Purdue University Indianapolis (IUPUI) / Resveratrol has been shown to inhibit cell growth and induce apoptosis, as well as augment chemotherapeutics and irradiation in multiple cancer types. However, it is unknown if resveratrol is beneficial for treating drug-resistant cancer cells. To study the effects of resveratrol in triple negative breast cancer cells that are resistant to the common cancer drug, paclitaxel, a novel paclitaxel-resistant cell line was generated from the MDA-MB-231 breast cancer cell line. The resulting cell line, MDA-MB-231/PacR, exhibited a 12-fold increased resistance to paclitaxel but remained sensitive to resveratrol treatment. Resveratrol treatment reduced cell proliferation and colony formation and increased senescence and apoptosis in both the parental MDA-MB-231 and MDA-MB-231/PacR cell lines. Importantly, resveratrol treatment augments the effects of paclitaxel in both cell lines. The expression of the drug efflux transporter gene, MDR1, and the main metabolizing enzyme of paclitaxel gene, CYP2C8, was increased in the resistant cells. Moreover, pharmacological inhibition of the protein products of these genes, P-glycoprotein and CYP2C8, decreased paclitaxel resistance in the resistant but not in the parental cells, which suggests that the increase of these proteins are important contributors to the resistance of these cells. In conclusion, these studies imply that resveratrol, both alone and in combination with paclitaxel, may be useful in the treatment of paclitaxel-sensitive and paclitaxel-resistant triple negative breast cancers.