D. W. Howse1, A. Carter1, C. Morrissey2, J. Bibb1 1University Of Alabama at Birmingham,Surgery,Birmingham, Alabama, USA 2University Of Washington,Seattle, WA, USA
Introduction:
Prostate cancer is the most prevalent form of cancer and constitutes the 3rd leading cause of cancer related deaths among men. The standard initial treatment for prostate cancer is androgen deprivation therapy (ADT). Despite initial effectiveness, almost all prostate adenocarcinomas will become resistant to ADT over time. Once progressed to this stage, the cancer is then referred to as castration resistant prostate cancer (CRPC). CRPC has a very poor prognosis with a median overall survival of approximately one-year with 90% of patients developing metastasis. CRPC may be divided into two categories: CRPC, and CRPC with a neuroendocrine phenotype (CRPC-NE). CPRPC-NE is considered the most highly aggressive form of prostate cancer. Recently, we have shown that Cdk5, a non-traditional cyclin dependent kinase, contributes to the development and progression of many different types of neuroendocrine cancers. We hypothesize that Cdk5 and its downstream effector SUV39H1 contributes to the poor prognosis of CRPC.
SUV39H1 is a H3K9m3 methyltransferase that, when disrupted, results in the relaxation of heterochromatin as well as chromosome instability. Phosphorylation of SUV39H1 disrupts its binding to heterochromatin, leading to early replication and replication stress. This project aims to assess whether Cdk5 is involved in the progression of prostate cancer through phosphorylation-mediated loss of function of SUV39H1. We hypothesize that aberrant activation of Cdk5 drives the conversion of CRPC to CRPC-NE through an SUV39H1-dependent pathway and that Cdk5 is an effective target for drug therapy.
Methods:
FFPE sections were obtained from Dr. Colm Morrissey from the University of Washington. The sections were 5 microns thick and were analyzed for Cdk5, p35/p25, chromogranin A, and synaptophysin. Phosphomietics of serine 391 of SUV39H1 have been made to elucidate the phosphorylation capacity of CDK5 and SUV39H1 as well as to transfect into cells to determine the effect on cell growth and migration.
Results:
Immunohistochemistry (IHC) illustrated that Cdk5 as well as its activators, p35/25, are present in patients that present with CRPC-NE. PC-3 cells (CRPC) exhibit expression of all of the required proteins for Cdk5 to phosphorylate SUV39H1.
Conclusion:
We have shown that the essential components in the Cdk5-SUV39H1 pathway are present in human tumors. Current studies with novel Cdk5 inhibitors, phosphorylation state-specific antibodies, and phosphomimetics will determine if SUV39H1 is required for the conversion of CRPC to CRPC-NE and the mechanisms responsible. Thus, we are providing new insights into the transdifferentiation from CRPC to CRPC-NE, toward the goal of finding treatment approaches for this most challenging form of cancer.