Retinoic acid receptor γ is a therapeutically targetable driver of growth and survival in prostate cancer

Background Prostate cancer (PC) tissue contains all‐trans retinoic acid (ATRA) at a very low level (10−9 M), at least an order of magnitude lower than in adjacent normal healthy prostate cells or benign prostate hyperplasia. When this is coupled with deregulated expression of the intracellular lipid‐binding proteins FABP5 and CRABP2 that is frequently found in PC, this is likely to result in the preferential delivery of ATRA to oncogenic PPARβ/δ rather than retinoic acid receptors (RARs). There are three isotypes of RARs (RARα, RARβ, and RARγ) and recent studies have revealed discrete physiological roles. For example, RARα and RARγ promote differentiation and self‐renewal, respectively, which are critical for proper hematopoiesis. Aims We have previously shown that ATRA stimulates transactivation of RARγ at sub‐nanomolar concentrations (EC50 0.24 nM), whereas an 80‐fold higher concentration was required for RARα‐mediated transactivation (EC50 19.3 nM). Additionally, we have shown that RAR pan‐antagonists inhibit the growth of PC cells (at 16‐34 nM). These findings, together with the low level of ATRA in PC, led us to hypothesize that RARγ plays a role in PC pathogenesis and that RARγ‐selective antagonism may be an effective treatment. Methods and results We found that concentrations of 10−9 M and below of ATRA promoted survival/proliferation and opposed adipogenic differentiation of human PC cell lines by a mechanism that involves RARγ. We also found that a RARγ‐selective antagonist (AGN205728) potently induced mitochondria‐dependent, but caspase‐independent, cell death in PC cell lines. Furthermore, AGN205728 demonstrated synergism in killing PC cells in combination with cytotoxic chemotherapeutic agents. Conclusion We suggest that the use of RARγ‐selective antagonists may be effective in PC (and potentially other cancers), either as a single agent or in combination with cytotoxic chemotherapy

The biguanide polyamine analog verlindamycin promotes differentiation in neuroblastoma via induction of antizyme

Deregulated polyamine biosynthesis is emerging as a common feature of neuroblastoma and drugs targeting this metabolic pathway such as DFMO are in clinical and preclinical development. The polyamine analog verlindamycin inhibits the polyamine biosynthesis pathway enzymes SMOX and PAOX, as well as the histone demethylase LSD1. Based on our previous research in acute myeloid leukemia (AML), we reasoned verlindamycin may also unblock neuroblastoma differentiation when combined with all-trans-retinoic acid (ATRA). Indeed, co-treatment with verlindamycin and ATRA strongly induced differentiation regardless of MYCN status, but in MYCN-expressing cells, protein levels were strongly diminished. This process was not transcriptionally regulated but was due to increased degradation of MYCN protein, at least in part via ubiquitin-independent, proteasome-dependent destruction. Here we report that verlindamycin effectively induces the expression of functional tumor suppressor—antizyme via ribosomal frameshifting. Consistent with previous results describing the function of antizyme, we found that verlindamycin treatment led to the selective targeting of ornithine decarboxylase (the rate-limiting enzyme for polyamine biosynthesis) as well as key oncoproteins, such as cyclin D and Aurora A kinase. Retinoid-based multimodal differentiation therapy is one of the few interventions that extends relapse-free survival in MYCN-associated high-risk neuroblastoma and these results point toward the potential use of verlindamycin in this regimen.Output Status: Forthcoming/Available Onlin

What Inhibits Natural Killers’ Performance in Tumour

Natural killer cells are innate lymphocytes with the ability to lyse tumour cells depending on the balance of their activating and inhibiting receptors. Growing numbers of clinical trials show promising results of NK cell-based immunotherapies. Unlike T cells, NK cells can lyse tumour cells independent of antigen presentation, based simply on their activation and inhibition receptors. Various strategies to improve NK cell-based therapies are being developed, all with one goal: to shift the balance to activation. In this review, we discuss the current understanding of ways NK cells can lyse tumour cells and all the inhibitory signals stopping their cytotoxic potential