Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively kill tumor cells. TRAIL resistance in cancers is associated with aberrant expression of the key components of the apoptotic program. However, how these components are regulated at the epigenetic level is not understood. In this study, we investigated novel epigenetic mechanisms regulating TRAIL response in glioblastoma multiforme (GBM) cells by a short-hairpin RNA loss-of-function screen. We interrogated 48 genes in DNA and histone modification pathways and identified KDM2B, an H3K36-specific demethylase, as a novel regulator of TRAIL response. Accordingly, silencing of KDM2B significantly enhanced TRAIL sensitivity, the activation of caspase-8, -3 and -7 and PARP cleavage. KDM2B knockdown also accelerated the apoptosis, as revealed by live-cell imaging experiments. To decipher the downstream molecular pathways regulated by KDM2B, levels of apoptosis-related genes were examined by RNA-sequencing upon KDM2B loss, which revealed derepression of proapoptotic genes Harakiri (HRK), caspase-7 and death receptor 4 (DR4) and repression of antiapoptotic genes. The apoptosis phenotype was partly dependent on HRK upregulation, as HRK knockdown significantly abrogated the sensitization. KDM2B-silenced tumors exhibited slower growth in vivo. Taken together, our findings suggest a novel mechanism, where the key apoptosis components are under epigenetic control of KDM2B in GBM cells.
The spread of cancer to bone is invariably fatal, with complex cross-talk between tumor cells and the bone microenvironment responsible for driving disease progression. By combining in silico analysis of patient datasets with metabolomic profiling of prostate cancer cells cultured with bone cells, we demonstrate the changing energy requirements of prostate cancer cells in the bone microenvironment, identifying the pentose phosphate pathway (PPP) as elevated in prostate cancer bone metastasis, with increased expression of the PPP rate-limiting enzyme glucose-6-phosphate dehydrogenase (G6PD) associated with a reduction in progression-free survival. Genetic and pharmacologic manipulation demonstrates that G6PD inhibition reduces prostate cancer growth and migration, associated with changes in cellular redox state and increased chemosensitivity. Genetic blockade of G6PD in vivo results in reduction of tumor growth within bone. In summary, we demonstrate the metabolic plasticity of prostate cancer cells in the bone microenvironment, identifying the PPP and G6PD as metabolic targets for the treatment of prostate cancer bone metastasis.
Cabergoline is an orally administered synthetic dopamine agonist that is used for the treatment of hyperprolactinemia, Parkinson’s disease and antipsychotic-induced prolactin elevation. One of the main characteristics of cabergoline is its long duration of effect. It is highly effective in suppressing prolactin levels up to 21 days after a single 1 mg oral dose. The prolonged elimination half-life offers an advantage of once-daily dosing, but it might be a handicap in terms of washout of adverse effects such as psychosis. Cabergoline has been associated with adverse reactions consistent with other dopaminergic agonists including cardiovascular, gastrointestinal and neuropsychiatric effects. It is known that dopaminergic treatment is a remarkable risk factor for psychosis. A number of reports implicate dopamine agonists in the development of psychosis, but there is no knowledge in the literature of dopamine agonist-induced mania. In this case, we report the first manic episode occurring after cabergoline use for hyperprolactinemia treatment. In susceptible individuals, cabergoline can cause manic episodes and cabergoline should be used more carefully considering the risk–benefit ratio.
Androgen receptor (AR) splice variants are described as one of the potential drivers of lethal castration-resistant prostate cancer. Androgen receptor splice variant 7 (ARv7) is the most commonly observed isoform and strongly correlates with resistance to second-generation antiandrogens. Despite this clinical evidence, the interplay between ARv7 and the highly expressed full-length AR (ARfl) remains unclear. In this work we show that ARfl/ARv7 heterodimers readily form in the nucleus via an intermolecular N/C interaction that brings the four termini of the proteins in close proximity. Combining FRET and FRAP we demonstrate that these heterodimers undergo conformational changes following DNA binding indicating dynamic nuclear receptor interaction. Although transcriptionally active, ARv7 can only form short-term interactions with DNA at highly accessible, high-occupancy ARfl binding sites. Dimerization with ARfl does not affect ARv7 binding dynamics suggesting that DNA binding occupancy is determined by the individual protein monomers and not the homo- or heterodimer complex. Overall, these biophysical studies reveal detailed properties of ARv7 dynamics as both a homodimer or heterodimer with ARfl.
Whilst treatment of multiple myeloma (MM) with daratumumab significantly extend patient lifespan, resistance to therapy is inevitable. ISB 1342 was designed to target MM cells from patients with relapsed/refractory MM (r/rMM) displaying lower sensitivity to daratumumab. ISB 1342 is a bispecific antibody with a high affinity Fab binding to CD38 on tumor cells on a different epitope than daratumumab and a detuned scFv domain affinity binding to CD3ε on T-cells, to mitigate the risk of life-threatening cytokine release syndrome, using the Bispecific Engagement by Antibodies based on the TCR (BEAT®) platform. In vitro, ISB 1342 efficiently killed cell lines with different levels of CD38 including those with a lower sensitivity to daratumumab. In a killing assay, wherein multiple modes of action were enabled, ISB 1342 showed higher cytotoxicity towards MM cells compared to daratumumab. This activity was retained when used in sequential or concomitant combinations with daratumumab. The efficacy of ISB 1342 was maintained in daratumumab-treated bone marrow patient samples showing lower sensitivity to daratumumab. ISB 1342 induced complete tumor control in two therapeutic mouse models, unlike daratumumab. Lastly, in cynomolgus monkeys, ISB 1342 displayed an acceptable toxicology profile. These data suggest that ISB 1342 may be an option in patients with r/rMM refractory to prior anti-CD38 bivalent monoclonal antibody therapies. It is currently developed in a phase 1 clinical study.
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