Prostate cancer is the second leading cause of cancer deaths in the United States and remains a significant health concern for men throughout the world. Despite the discovery of promising immunotherapeutic strategies,...Prostate cancer is the second leading cause of cancer deaths in the United States and remains a significant health concern for men throughout the world. Despite the discovery of promising immunotherapeutic strategies, curative outcomes remain elusive. We have investigated eosinophils as potential anti-cancer effector cells, and have reported the ability of their toxic granular proteins (MBP, EPO, ECP, EDN) to inhibit prostate tumor cell growth?in vitro. This study investigates the effect of eosinophil MBP extract on the expression of oncogenes p53, bcl-xl, bax, and c-myc, which modulate tumor growth, proliferation, and apoptosis. Briefly, granular proteins were differentially extracted from GRC.014.22 and GRC.014.24, eosinophilic cell lines established in our laboratory from a patient with moderate asthma. Protein extracts were fractionated on Sephadex G-50 columns, and prostate tumor cell lines DU-145, LNCaP, PC-3, and HPC8L (established in our laboratory from a tumor resected from an African American patient) were treated with MBP extracts from the pooled third peaks. Colony formation and monolayer cell growth inhibition assays were used to evaluate the protein’s growth inhibitory activity against prostate tumor cells;and gene expression analyses, to determine p53, bcl-xl, bax, and c-myc oncogene expression. We show that the granular proteins were potent in their action on HPC8L, inhibiting colony formation in a dose-dependent manner. Treated prostate tumor cell lines trended toward apoptosis-induction, as evident in bcl-xl/bax ratios < 1, increased p53 expression, and up or downregulation of c-myc. These preliminary results demonstrate the growth inhibitory potential of eosinophil granular proteins and strongly support the hypothesis that eosinophils modulate the expression of oncogenes associated with prostate tumor proliferation and apoptosis. More importantly, this study offers insights into possible applications of eosinophilic mediators in oncogenic-targeted prostate cancer treatment strategies and demonstrates the potential therapeutic implications of enhancing eosinophilic activity in prostate cancer.展开更多
文摘Prostate cancer is the second leading cause of cancer deaths in the United States and remains a significant health concern for men throughout the world. Despite the discovery of promising immunotherapeutic strategies, curative outcomes remain elusive. We have investigated eosinophils as potential anti-cancer effector cells, and have reported the ability of their toxic granular proteins (MBP, EPO, ECP, EDN) to inhibit prostate tumor cell growth?in vitro. This study investigates the effect of eosinophil MBP extract on the expression of oncogenes p53, bcl-xl, bax, and c-myc, which modulate tumor growth, proliferation, and apoptosis. Briefly, granular proteins were differentially extracted from GRC.014.22 and GRC.014.24, eosinophilic cell lines established in our laboratory from a patient with moderate asthma. Protein extracts were fractionated on Sephadex G-50 columns, and prostate tumor cell lines DU-145, LNCaP, PC-3, and HPC8L (established in our laboratory from a tumor resected from an African American patient) were treated with MBP extracts from the pooled third peaks. Colony formation and monolayer cell growth inhibition assays were used to evaluate the protein’s growth inhibitory activity against prostate tumor cells;and gene expression analyses, to determine p53, bcl-xl, bax, and c-myc oncogene expression. We show that the granular proteins were potent in their action on HPC8L, inhibiting colony formation in a dose-dependent manner. Treated prostate tumor cell lines trended toward apoptosis-induction, as evident in bcl-xl/bax ratios < 1, increased p53 expression, and up or downregulation of c-myc. These preliminary results demonstrate the growth inhibitory potential of eosinophil granular proteins and strongly support the hypothesis that eosinophils modulate the expression of oncogenes associated with prostate tumor proliferation and apoptosis. More importantly, this study offers insights into possible applications of eosinophilic mediators in oncogenic-targeted prostate cancer treatment strategies and demonstrates the potential therapeutic implications of enhancing eosinophilic activity in prostate cancer.
