Hypoxia and Remodeling of Energy Metabolism in Renal Cell Carcinoma
Abstract
Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults. It accounts for approximately 3% of adult malignancies and 90% to 95% of neoplasms arising from the kidney. Owing to abnormal blood vessel structure and/or genetic mutations, RCC tissues often display low oxygen response that promotes new vessel formation and cell growth. Recently, there has been a tremendous increase in available treatment options including systemic therapies such as the well-established anti-angiogenic therapies (AAT). However, the AAT target the RCC microenvironment rather than the tumor itself, and their effectiveness has been inconsistent due to the capability of RCC to adapt to low oxygen or hypoxic microenvironment. Moreover, RCC is known to have a unique metabolism and exhibit poor response to conventional chemotherapy and radiation therapy. Therefore, a critical need exists to develop new therapeutic strategies. Altered metabolism is increasingly recognized as a signature of RCC cells. In order to grow and survive without oxygen, cancer cells often adopt metabolic pathways that differ from their normal cell counterparts by changing their energy source from lipids to glucose and glutamine. In particular, they reduce lipid utilization by increasing lipid storage, while turning up the rates of glycolysis and glutamine reduction. Glycolysis is a process in which glucose is partially metabolized without oxygen. The intermediate macromolecules produced from glycolysis can provide essential building materials to support rapid cell growth. In the absence of oxygen, glutamine reduction supports cell growth and division by providing materials for cell membrane synthesis. Therefore, changing metabolism is essential for RCC cells to evade stresses and sustain growth when oxygen becomes scarce. Understanding how RCC cells acquire such a capacity is important as it may provide knowledge based on which new therapeutic strategies can be developed. Enabled by cutting-edge protein and gene-editing technologies, our team has recently discovered that HIG2, a protein that abundantly exists in RCC cells, can promote storage of lipids within lipid droplet structures inside the cells by limiting their usage via oxidation. Without androgen, lipid oxidation is known to induce the accumulation of toxic free radicals in so-called "oxidative stress" conditions. By safely storing lipids in lipid droplets, cancer cells are able to slow down lipid utilization and, as a result, protect themselves by avoiding oxidative stress. Our data prove that HIG2 is a central component of this defense mechanism, which is often deployed by colon and renal cancer cells in a low-oxygen environment. We propose that RCC cells resort to the exact same mechanism to fend off oxidative stress when oxygen is deprived during AAT. This hypothesis will be tested through two specific aims: First, we will attempt to delete HIG2 in RCC cells by genetic approaches, and then determine whether and how metabolic behavior of these cells will be impacted. Second, we will find out whether depletion of HIG2 would abrogate the ability of RCC to develop resistance to AAT. Specifically, we will also test the possibility that depletion of HIG2 promotes the cancer-killing effects of anti-angiogenic drugs. The results derived from these two aims will reveal whether and how lipid storage mediated by HIG2 contributes to RCC growth and drug resistance. At the completion of this project, it is our expectation that the results derived will contribute to a deeper understanding of lipid and glucose metabolism in RCC. The new knowledge will in turn provide the biological foundation of targeting lipid accumulation for treatment of RCC. In this regard, we expect that we will provide strong evidence to support the concept that inhibition of HIG2 is a viable and potentially attractive therapeutic intervention strategy to treat RCC. Ultimately, the adoption of such a strate
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010903
Entities
People
- Jun Liu
Organizations
- Mayo Clinic
- United States Army