HSD10 Regulates Cancer Cell Growth and Resistance to Cell Death

Abstract

Dysfunction or deregulation of certain cellular processes is commonly used to distinguish known illnesses into separate and unique disease states. Although each cancer type is individually distinct, most cancers initially occur due to genomic mutations of oncogenes and tumor suppressor genes, leading to enhancement or disruption of specific cellular processes, including mitochondrial-mediated events. As an organelle necessary for both cell survival and cell death, the mitochondrion is involved in a variety of diseases, including cancer. Specific alterations to mitochondrial DNA in cancer can result in enhanced proliferation and avoidance of cell death pathways. Thus, alterations to mitochondria function often increase the likelihood of tumor progression. In this dissertation, the role of a mitochondrial enzyme, 17β-hydroxysteroid dehydrogenase type 10 (HSD10), was examined in relation to cancer progression. In rat adrenal gland tumor cells, upregulation of HSD10 correlated with increased cell growth rate and tumor growth in mice, enhanced energy metabolism, and protection against oxidative stress-induced cell death. Downregulation of HSD10 in the rat adrenal gland tumor cells resulted in decreased cell growth rate, reduced mitochondrial bioenergetics, and increased vulnerability to cell death induction under both baseline and oxidative stress conditions. Reductions in cell growth rate and energy metabolism were also observed upon HSD10 knockdown in T47D human breast cancer cells, which supports the role of HSD10 in cancer across two different cancer types and species. Furthermore, overexpression of HSD10 did not transform MCF10A breast cells, providing evidence that HSD10 may not be a tumor-initiating factor. Together, the data suggest that upregulation of HSD10 promotes cell growth and resistance to stress-induced cell death specifically in cancer cells.