Choline Kinase Alpha as an Androgen Receptor Chaperone and Prostate Cancer Therapeutic Target

BACKGROUND: The androgen receptor (AR) is a major drug target in prostate cancer (PCa). We profiled the AR-regulated kinome to identify clinically relevant and druggable effectors of AR signaling.

METHODS: Using genome-wide approaches, we interrogated all AR regulated kinases. Among these, choline kinase alpha (CHKA) expression was evaluated in benign (n = 195), prostatic intraepithelial neoplasia (PIN) (n = 153) and prostate cancer (PCa) lesions (n = 359). We interrogated how CHKA regulates AR signaling using biochemical assays and investigated androgen regulation of CHKA expression in men with PCa, both untreated (n = 20) and treated with an androgen biosynthesis inhibitor degarelix (n = 27). We studied the effect of CHKA inhibition on the PCa transcriptome using RNA sequencing and tested the effect of CHKA inhibition on cell growth, clonogenic survival and invasion. Tumor xenografts (n = 6 per group) were generated in mice using genetically engineered prostate cancer cells with inducible CHKA knockdown. Data were analyzed with χ(2) tests, Cox regression analysis, and Kaplan-Meier methods. All statistical tests were two-sided.

RESULTS: CHKA expression was shown to be androgen regulated in cell lines, xenografts, and human tissue (log fold change from 6.75 to 6.59, P = .002) and was positively associated with tumor stage. CHKA binds directly to the ligand-binding domain (LBD) of AR, enhancing its stability. As such, CHKA is the first kinase identified as an AR chaperone. Inhibition of CHKA repressed the AR transcriptional program including pathways enriched for regulation of protein folding, decreased AR protein levels, and inhibited the growth of PCa cell lines, human PCa explants, and tumor xenografts.

CONCLUSIONS: CHKA can act as an AR chaperone, providing, to our knowledge, the first evidence for kinases as molecular chaperones, making CHKA both a marker of tumor progression and a potential therapeutic target for PCa.

On the conservatism of post-Jungian criticism: competing concepts of the symbol in Freud, Jung and Walter Benjamin

The renewed interest in analytical psychology by academics working in the humanities has led to the emergence of a post-Jungian field of cultural criticism, at the theoretical core of which stands Jung's theory of symbolism. This article examines the centrality of symbolism to both Freud and Jung's psychology and explains how the differing concepts of the symbol lead to their divergent theories of interpretation in psychology and art criticism. Acknowledging the advantages of Jung's more expansive account of the symbol, it argues that Walter Benjamin's critical engagement with Jung nonetheless provides a useful correction to the problematic conservatism inherent to his concept of the symbol and its contemporary application.

Being Taught by Biesta

What are we to do with the writing of Biesta? Raising the same question in relation to Jacques Rancière, in a 2010 study co-authored with Charles Bingham, Gert J. J. Biesta takes the writer of ‘a short, disparaging review of …The Ignorant Schoolmaster’ to task for “schooling” Rancière on the inadequacies of the book reviewed (Biesta & Bingham 2010, 145-148). Readers of Biesta cheering on from the sidelines at this point are placed in an uncomfortable double bind if they are to take this suggestion seriously when reviewing his own work. We are not, Biesta and Bingham (2010, 148) suggest, to police interpretations like a vigilant schoolmaster in possession of superior knowledge but rather ‘proceed as a child who looks forward to the sound of the bell’ and to ‘speak as if truant’.

Charles e Ray Eames, o casamento entre razão e emoção no design

O racionalismo surge como uma corrente filosófica, cuja operação mental e lógica é evidenciada. Sendo a principal característica do pensamento moderno o método, a bauhaus representa para o design a forma como a indústria se despiu dos ornamentos, buscando o ideal de forma e função. Numa corrente contemporânea, o design emocional retoma, além das funções que um objeto pode ter, estéticas, práticas e simbólicas, também as emocionais de identificação, fazendo rever os métodos. Este artigo faz uma relação deste contexto com a forma brilhante com que o casal Charles e Ray Eames, criou um método absolutamente emocional para a criação do design, iniciando, com a invenção do contraplacado, e depois com acesso a diversas tecnologias advindas do pós-guerra, um processo muito interessante de construção de design, aliando arte e técnica, produzindo assentos atemporais, encontrados facilmente no mundo contemporâneo.