The efficacy of dmrFABP5 on suppressing the malignant progression of prostate cancer cells either singly or in combination with drugs in use and relevant molecular mechanisms

Abstract

Standard prostate cancer (PCa) treatment options, including chemotherapy and androgen deprivation therapy (ADT) with drugs like docetaxel and enzalutamide, eventually become ineffective, necessitating the exploration of new therapeutic strategies, such as the recently proposed Anti-FABP5 therapy with its bio-inhibitor dmrFABP5. This study is aimed to assess the synergistic effects of combining dmrFABP5 with either docetaxel or enzalutamide in experimental PCa treatment. We found that the treatment of dmrFABP5 combined with docetaxel in androgen-independent Du145 and androgen-responsive 22RV1 cells exhibited a synergistic effect as determined by the Combination Index (CI) assessed with CompuSyn software and resulted in a significant reduction in the malignant characteristics of the cells. The treatment of 22RV1 cells with dmrFABP5 combined with enzalutamide produced a synergistic suppression effect on the malignant characteristics of the cells. To study the molecular mechanisms behind the synergistic interactions, we investigated the changes in expression levels of a number of proteins related to FABP5-initiated signal transduction pathways and those related to tumorigenicity, apoptosis, and angiogenesis in DU145 and 22RV1 cells. The results showed that the combination treatment of dmrFABP5 with docetaxel promoted apoptosis with disrupted some apoptosis factors, decreased angiogenesis factor, suppressed fatty acid receptor and reduced the level of Sp1. In 22RV1 cells, apart from similar aforementioned enhancement effect, a synergistic suppression on the expression of AR and AR-V7 was also observed. Furthermore, the combination of dmrFABP5 with enzalutamide significantly suppressed not only the same pathways, except apoptosis, as those in 22RV1 cells, but also the expression of AR and AR-V7. RNA profiling of DU145 treated with dmrFABP5 revealed the most enriched pathways and differential gene expression, providing insight into the underlying mechanisms of dmrFABP5 action. These findings provided a theoretical basis for a therapy to combine dmrFABP5 with either docetaxel or enzalutamide as a treatment strategy for prostate cancer.