Targeting NUAK2 to Mitigate Obesity-Enhanced Prostate Cancer Growth and Metastasis
Abstract
Obesity is linked with greater risk of high-grade prostate cancer, recurrence after therapy, metastases, and prostate cancer-specific death. We exploited the link between obesity and the increased chances of dying from prostate cancer to identify potential drug targets. To this end, we performed a kinase screen in tumors grown in mice fed high-fat western diets. Kinases are enzymes involved in protein-protein signal transduction and are high-value therapeutic targets because they are very druggable. Our screen identified that the protein NUAK Family Kinase 2 (NUAK2) is essential for tumors grown in mice on high-fat western diets. This suggests that, if we inhibit NUAK2 activity, it may reduce the negative effects of obesity on prostate cancer growth and progression. Subsequent analysis of human prostate cancer specimens revealed NUAK2 is upregulated in prostate cancer tissue vs. normal benign prostate tissue. Moreover, we found NUAK2 target is elevated in metastatic prostate cancer biopsies compared to organ-confined tumors, suggesting elevated NUAK2 enzymatic activity in prostate cancer metastasis. In normal cells, NUAK2 responds to various cellular stresses. However, in some cancers, such as breast, liver, and melanoma, NUAK2 has been shown to have a pro-tumorigenic role. Yet, NUAK2 is widely understudied, including in prostate cancer. Our preliminary data show that genetic depletion of NUAK2 or pharmacological inhibition with NUAK2 small molecule inhibitors slowed prostate cancer spheroid growth. Moreover, small molecule inhibitors prevented prostate cancer cell migration and invasion. Interestingly, we found that addition of dietary fatty acids increased NUAK2 expression in prostate cancer cells and pharmacological inhibition of NUAK2 increased cell lipotoxicity. Our hypothesis is that NUAK2 is essential for obesity-enhanced progression of PC to metastatic disease. Thus, targeting NUAK2 may prevent the effects of obesity on PC progression by lowering the liptoxic threshold. We will conduct a number of preclinical genetic and pharmacological studies to determine whether NUAK2 mediates obesity-enhanced prostate cancer aggressiveness. If successful, our studies will validate and provide a therapeutic strategy against a molecular target (NUAK2) by which obesity makes PCs more aggressive and allows them to metastasize and cause prostate cancer mortality. This should be of significance to the Department of Defense, given the high prevalence of obesity in Veterans.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110854
Entities
People
- Everardo Macias
Organizations
- Duke University
- United States Army