tretinoin and juglone

Therapies for lethal castration-resistant prostate cancer (CRPC) are an unmet medical need. One mechanism underlying CRPC and resistance to hormonal therapies is the expression of constitutively active splice variant(s) of androgen receptor (AR-Vs) that lack its C-terminus ligand-binding domain. Transcriptional activities of AR-Vs and full-length AR reside in its N-terminal domain (NTD). Ralaniten is the only drug proven to bind AR NTD, and it showed promise of efficacy in Phase 1 trials. The peptidyl-prolyl isomerase Pin1 is frequently overexpressed in prostate cancer. Here we show that Pin1 interacted with AR NTD. The inhibition of Pin1 expression or its activity selectively reduced the transcriptional activities of full-length AR and AR-V7. Combination of Pin1 inhibitor with ralaniten promoted cell cycle arrest and had improved antitumor activity against CRPC xenografts in vivo compared to individual monotherapies. These findings support the rationale for therapy that combines a Pin1 inhibitor with ralaniten for treating CRPC.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Cycle Checkpoints; Cell Proliferation; Drug Resistance, Neoplasm; Enzyme Inhibitors; Humans; Male; Mice, Inbred NOD; Mice, SCID; Naphthoquinones; NIMA-Interacting Peptidylprolyl Isomerase; PC-3 Cells; Prostatic Neoplasms, Castration-Resistant; Protein Domains; Receptors, Androgen; Signal Transduction; Tretinoin; Tumor Burden; Xenograft Model Antitumor Assays

The Groucho/transducin-like Enhancer of split 1 (Gro/TLE1):Hes1 transcriptional repression complex acts in cerebral cortical neural progenitor cells to inhibit neuronal differentiation. The molecular mechanisms that regulate the anti-neurogenic function of the Gro/TLE1:Hes1 complex during cortical neurogenesis remain to be defined. Here we show that prolyl isomerase Pin1 (peptidyl-prolyl cis-trans isomerase NIMA-interacting 1) and homeodomain-interacting protein kinase 2 (HIPK2) are expressed in cortical neural progenitor cells and form a complex that interacts with the Gro/TLE1:Hes1 complex. This association depends on the enzymatic activities of both HIPK2 and Pin1, as well as on the association of Gro/TLE1 with Hes1, but is independent of the previously described Hes1-activated phosphorylation of Gro/TLE1. Interaction with the Pin1:HIPK2 complex results in Gro/TLE1 hyperphosphorylation and weakens both the transcriptional repression activity and the anti-neurogenic function of the Gro/TLE1:Hes1 complex. These results provide evidence that HIPK2 and Pin1 work together to promote cortical neurogenesis, at least in part, by suppressing Gro/TLE1:Hes1-mediated inhibition of neuronal differentiation.

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Carrier Proteins; Cell Differentiation; Cell Line, Tumor; Cells, Cultured; Cerebral Cortex; HEK293 Cells; Homeodomain Proteins; Humans; Mice; Naphthoquinones; Neural Stem Cells; Neurogenesis; NIMA-Interacting Peptidylprolyl Isomerase; Peptidylprolyl Isomerase; Protein Serine-Threonine Kinases; Repressor Proteins; Transcription Factor HES-1; Tretinoin