ESR Project 9: TRIB-mediated regulation of metabolism in prostate epithelium and cancer lesions
Prostate cancer is one of the most commonly diagnosed cancers in males, worldwide. The development of this male malignancy is generally attributed to a combination of risk factors namely; genetics, environmental factors, hormonal imbalance, age, and race. Prostate cancer is a hormone-dependent cancer, and sex steroid hormones androgens play a crucial role in disease progression, which renders androgen deprivation therapy (ADT) the standard treatment for advanced stages of disease. However, prostate cancer cells develop resistance and growth becomes independent of the circulating androgen levels, thereby leading to increased disease progression. Obesity, which has risen alarmingly within the past years, recently emerged as an important metabolic alteration influencing the aggressiveness of prostate cancer. On the other hand, androgens are also known to have an influence in metabolic alterations that sustain cell growth and survival, therefore a hallmark which shapes the progression of prostate cancer.
Tribbles (TRIB) proteins have been shown to have a key role in controlling immunity, metabolism and cancer. TRIB1 locus variants are known to be associated with altered blood cholesterol and triglyceride levels which is required for cell proliferation. Database mining has also revealed that TRIB1 expression is tightly associated with compounds affecting expression of genes regulating cholesterol synthesis and oxidative phosphorylation. However, it is not known whether this represents an adaptive response and/or high expression in a specific cell type. Moreover, it remains to be clarified whether TRIB1 is the effector or whether its expression is affected by the androgenic modulation of prostate cancer metabolism. This ERS9 project aims to define the biological relationship of androgens, metabolism and TRIB proteins in prostate cancer which remains largely elusive. This project will mainly focus on the assessment of TRIB1 and TRIB3 proteins.
Overall, the key objectives for this study are:
1. To elucidate the roles of TRIB1 and TRIB3 in the regulation of androgen-mediated metabolic adaptation in prostate cancer, exploring the effects of androgens and anti-androgens on TRIB1 and TRIB3 expression. Additionally, measure the expression of key genes regulating oxidative phosphorylation, cholesterol and triglyceride availability, focusing on targets such as PPARs, FASN, Hmgcr, PCSK9, ACC etc.
2. Further characterise the effects of TRIB1 and TRIB3 silencing via shRNA, on androgens and anti-androgen-mediated effects on the expression of these gene sets, additionally to their metabolome.
3. Use murine models for prostate cancer to validate the in-vitro findings in a relevant pathophysiological disease system. The mechanisms of androgen-TRIB1 and -TRIB3 mediated regulation of oxidative phosphorylation, fatty acid, cholesterol and triglyceride metabolism will be evaluated. Furthermore, identification of E3 Ubiquitin ligases that promote TRIB1 degradation will be examined in tissues, cells and lesions of prostate cancer mouse models. Lastly, testing their functionality on TRIB1-mediated gene expression activities for therapeutic purposes.