Discipline: Biological Sciences
Subcategory: Cancer Research
Leslie McClinton, III - Tougaloo College
Co-Author(s): Surendra Gulla, Ph.D., University at Buffalo, Jacobs School of Medicine and Biomedical Sciences, Department of Medicine, Division of Hematology and Oncology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, NY; Remi Adelaiye-Ogala, Ph.D., University at Buffalo, Jacobs School of Medicine and Biomedical Sciences, Department of Medicine, Division of Hematology and Oncology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, NY.
Prostate cancer (PC) second leading cause of cancer related deaths in men in the United States. This disease is driven by androgen receptor (AR) activity and the mainstay therapeutic option is AR targeted therapy. However, despite success in previous clinical studies, patients develop resistance and progression occurs to castration-resistant prostate cancer (CRPC). An emerging mechanism of resistance to AR targeted therapy is induction of compensatory hormone nuclear receptor, the glucocorticoid receptor (GR). Recently published data from research lab shows that posttranslational modification (PTM) mechanisms by phosphorylation via PI3K/AKT signaling pathway led to blockade of the induction of GR expression. Recently, preclinical, and clinical data implicated induction of GR expression and activity to be upregulated in treatment resistant CRPC. Recently published data from research lab shows that inhibition of PI3K/AKT signaling led to blockade of the induction of GR expression suggesting that pro-oncogenic GR expression and activity may be modulated via posttranslational modification (PTM) mechanisms such as phosphorylation even in the absence of ligand. However, this specific role of PTM in the induction of GR in CRPC is unknown. Our hypothesis suggested that the induction of GR following AR blockade, is modulated by phosphorylation via PI3K/AKT signaling pathway. We analyzed and selected PC cell lines (sensitive and resistant) that were treated with enzalutamide to determine GR expression and determinants by performing various downstream analyses (E.g., cell viability assay, qPCR, and protein and gene expression). Functional study (RIME: protein-protein interaction) was performed on PC and overexpressed GR cell lines that were treated with enzalutamide and inhibitors to determine GR expression by PTM. In conclusion our results demonstrated that our downstream analyses and functional study in our cell lines and PDX (Patient-Derived Xenograft) models showed there is an induction of GR expression and modulation by phosphorylation via PI3K/AKT signaling pathway activity following AR blockade. This is a potential therapeutic target for advanced PC, when AR targeted therapy becomes resistant. Ongoing studies (data brewing in the lab) will determine GR phosphorylation status in the following AR blockade in addition PDX models.
Funder Acknowledgement(s): This research is funded by the Collaborative Learning and Integrated Mentoring in the Bioscience Undergraduate Program (CLIMB -UP) and Institute for Strategic Enhancement of Educational Diversity (iSEED) at the University at Buffalo.
Faculty Advisor: Dr. Remi Adelaiye-Ogala, Ph.D., email@example.com
Role: My specific role in the project was to grow and treat our sensitive and resistance prostate cancer cells in cell culture and run a variety of downstream analyzes such as cell viability assay, qPCR, and protein and gene expression. These specific roles and my research helped contributed to the overall research mission. I validated previous studies my mentor has done that suggest that there is an induction of GR expression and activity following AR blockade. Overall, my contribution to the overall research mission of the lab helped the progression of potential therapeutic targets for advanced prostate cancer, when AR target therapy becomes resistant.