The interactive roles of Ca2+/calmodulin-dependent protein kinase kinase 2, nucleoporin 62, and the androgen receptor in prostate cancer cells
Kuroski, Laura A.
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Molecular mechanisms underlying the progression of prostate cancer (PCa) and the development of castrate resistant prostate cancer (CRPC) remain poorly understood. Studies have shown that Ca2+/Calmodulin-dependent Protein Kinase Kinase 2 (CaMKK2) is enriched in the nuclear fraction of C4-2, a CRPC cell model, compared to the nuclear fraction of its parental cell line LNCaP cells, an androgen sensitive PCa cell model. Additionally, studies have shown that CaMKK2 along with its downstream targets are playing a role in androgen receptor (AR) signaling pathways. I report here a new and unexpected component in AR transcriptional regulation and growth of CRPC cells, nucleoporin 62 (Nup62) a component of the nuclear pore complex (NPC). In C4-2 cells CaMKK2, Nup62, and the AR physically interact and are co-recruited to androgen response elements of AR target genes. Silencing of Nup62 expression by RNA interference (RNAi) technology significantly decreased AR transcriptional activity and expression of the AR target gene, prostate specific antigen (PSA). CaMKK2 silencing produced an equally significant decrease in AR transcriptional activity compared to Nup62 silencing as measured by an ARE-luciferase gene reporter assay. However, the combined silencing of Nup62 and CaMKK2 produced no further decreases in transcriptional activity beyond that produced by Nup62 and CaMKK2 alone, suggesting that there is a dual requirement of CaMKK2 and Nup62 to maintain AR transcriptional activity. Nup62 silencing slowed C4-2 cell growth rate and decreased percent cell viability. In a non-neoplastic prostatic cell model, RWPE-1 cells, Nup62 silencing produced a modest slowing of cell growth with no effect on percent cell viability. Studies have shown that both Nup 88 and 98 have previous links to cancer, but the silencing of these NPC proteins did not slow cell growth or decrease percent cell viability in C4-2 cells, suggesting a specific role for Nup62 in C4-2 cell growth as well as cell viability. Further studies to develop a complete understanding of the combined roles of CaMKK2, Nup62 and the AR in driving PCa progression could result in CaMKK2 and/or Nup62 being used clinically as diagnostic tools or treatment of PCa.