Mohamed Abdulla Abu el Maaty

Androgen deprivation therapy (ADT) is a cornerstone of prostate cancer (PCa) management. Although tumors initially regress, many progress to a hormone‐independent state termed castration‐resistant PCa (CRPC), for which treatment options are limited. We here report that the major luminal cell population in tumors of Pten ^(i)pe−/− mice, generated by luminal epithelial cell‐specific deletion of the tumor suppressor PTEN after puberty, is castration‐resistant and that the expression of inflammation and stemness markers is enhanced in persistent luminal cells. In addition, hypoxia‐inducible factor 1 (HIF1) signaling, which we have previously demonstrated to be induced in luminal cells of Pten ^(i)pe−/− mice and to promote malignant progression, is further activated. Importantly, we show that genetic and pharmacological inhibition of HIF1A sensitizes Pten‐deficient prostatic tumors to castration and provides durable therapeutic responses. Furthermore, HIF1A inhibition induces apoptotic signaling in human CRPC cell lines. Therefore, our data demonstrate that HIF1A in prostatic tumor cells is a critical factor that enables their survival after ADT, and identify it as a target for CRPC management.

Prostate cancer (PCa) is a leading cause of cancer-related deaths. The slow evolution of precancerous lesions to malignant tumors provides a broad time frame for preventing PCa. To characterize prostatic intraepithelial neoplasia (PIN) progression, we conducted longitudinal studies on Pten ^(i)pe−/− mice that recapitulate prostate carcinogenesis in humans. We found that early PINs are hypoxic and that hypoxia-inducible factor 1 alpha (HIF1A) signaling is activated in luminal cells, thus enhancing malignant progression. Luminal HIF1A dampens immune surveillance and drives luminal plasticity, leading to the emergence of cells that overexpress Transglutaminase 2 (TGM2) and have impaired androgen signaling. Elevated TGM2 levels in patients with PCa are associated with shortened progression-free survival after prostatectomy. Last, we show that pharmacologically inhibiting HIF1A impairs cell proliferation and induces apoptosis in PINs. Therefore, our study demonstrates that HIF1A is a target for PCa prevention and that TGM2 is a promising prognostic biomarker of early relapse after prostatectomy.

Anti- and protumoral effects of a vitamin D analog revealed at single-cell resolution.

A novel alkynyl phosphane gold(I) complex (trimethylphosphane)(3‐(1,3‐dimethylxanthine‐7‐yl)prop‐1‐yn‐1‐yl)gold(I) 1 displayed mutiple biological activites including selective proliferation inhibitory, anti‐metastatic, and anti‐angiogenic effects. The complex also induced effects related to aneuploidy in HCT‐116 colon carcinoma cells, which might be mainly ascribed to the dysfunction of mitochondrial bioenergetics and downregulation of glycolysis. Induction of aneuploidy beyond a critical level can provide an effective strategy to target cancer, in particular colorectal tumours with a low tolerance of aneuploidy, and could be of relevance for 1 and other metallodrugs.

Ein neuartiger Alkinylphosphan‐Gold(I)‐Komplex – (Trimethylphosphan)(3‐(1,3‐dimethylxanthin‐7‐yl)prop‐1‐in‐1‐yl)gold(I) (1) – zeigte eine Vielzahl biologischer Aktivitäten, darunter selektive proliferationshemmende, antimetastatische und antiangiogene Wirkungen. In HCT‐116‐Kolonkarzinomzellen induzierte der Komplex zudem mit Aneuploidie in Zusammenhang stehende Effekte, die hauptsächlich auf die Dysfunktion der mitochondrialen Bioenergetik und die Herunterregulierung der Glykolyse zurückgeführt werden konnten. Die Induktion von Aneuploidie über ein kritisches Maß hinaus kann eine wirksame Strategie zur Bekämpfung von Krebs darstellen, besonders bei kolorektalen Tumoren mit einer geringen Toleranz für Aneuploidie. Dies könnte für 1 und andere Metallwirkstoffe von Bedeutung sein.

The tumor suppressor p53 has a diverse mutational profile in human malignancies, which is known to influence the potency of various chemotherapeutics such as platins and anti-metabolites. However, the impact of the mutations in the TP53 gene (coding for p53) on the anti-cancer efficacy of gold complexes remains incompletely understood. We therefore investigated the anti-tumor properties of a gold(I) N-heterocyclic carbene (NHC) complex–termed MC3–in human colorectal cancer (CRC) cell lines encompassing three different p53 variations: HCT116 wild-type (WT), HCT116 p53-/-, and HT-29 (mutant; R273H). MC3 treatment induced intracellular reactive oxygen species (ROS) levels, and p21 expression, leading to cell cycle arrest in all cell lines, regardless of their p53 status. The pro-apoptotic response, however, was found to occur in a p53-dependent manner, with WT p53 harboring cells showing the highest responsiveness. Additionally, p73, which was speculated to substitute p53 in p53-deficient cells, was found to be markedly reduced with MC3 treatment in all the cell lines and knocking down its levels did not impact MC3’s anti-tumor effects in HCT116 p53-/- cells. Collectively, our results suggest that this small molecule has anti-cancer properties in the context of deficient or mutant p53 and may therefore have chemotherapeutic potential for clinical application.

We have previously identified 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], the bioactive form of vitamin D₃, as a potent regulator of energy-utilization and nutrient-sensing pathways in prostate cancer cells. In the current study, we investigated the effects of 1,25(OH)₂D₃ on breast cancer (BCa) cell metabolism using cell lines representing distinct molecular subtypes, luminal (MCF-7 and T-47D), and triple-negative BCa (MDA-MB-231, MDA-MB-468, and HCC-1143). 1,25(OH)₂D₃’s effect on BCa cell metabolism was evaluated by employing a combination of real-time measurements of glycolysis/oxygen consumption rates using a biosensor chip system, GC/MS-based metabolomics, gene expression analysis, and assessment of overall energy levels. The influence of treatment on energy-related signaling molecules was investigated by immunoblotting. We show that 1,25(OH)₂D₃ significantly induces the expression and activity of the pentose phosphate pathway enzyme glucose-6-phosphate dehydrogenase (G6PD) in all BCa cell lines, however differentially influences glycolytic and respiratory rates in the same cells. Although 1,25(OH)₂D₃ treatment was found to induce seemingly anti-oxidant responses in MCF-7 cells, such as increased intracellular serine levels, and reduce the expression of its putative target gene thioredoxin-interacting protein (TXNIP), intracellular reactive oxygen species levels were found to be elevated. Serine accumulation in 1,25(OH)₂D₃-treated cells was not found to hamper the efficacy of chemotherapeutics, including 5-fluorouracil. Detailed analyses of the nature of TXNIP’s regulation by 1,25(OH)₂D₃ included genetic and pharmacological inhibition of signaling molecules and metabolic enzymes including AMP-activated protein kinase and G6PD, as well as by studying the ITCH (E3 ubiquitin ligase)-TXNIP interaction. While these investigations demonstrated minimal involvement of such pathways in the observed non-canonical regulation of TXNIP, inhibition of estrogen receptor (ER) signaling by tamoxifen mirrored the reduction of TXNIP levels by 1,25(OH)₂D₃, demonstrating that the latter’s negative regulation of ER expression is a potential mechanism of TXNIP modulation. Altogether, we propose that regulation of energy metabolism contributes to 1,25(OH)₂D₃’s anti-cancer effects and that combining 1,25(OH)₂D₃ with drugs targeting metabolic networks in tumor cells may lead to synergistic effects.

Thioredoxin-interacting protein (TXNIP) was originally identified in HL-60 cells as the vitamin D₃ upregulated protein 1, and is now known to be involved in diverse cellular processes, such as maintenance of glucose homeostasis, redox balance, and apoptosis. Besides the initial characterization, little is known about if and how 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] induces TXNIP expression. We therefore screened multiple cancerous cell lines of different tissue origins, and observed induction, repression, or no change in TXNIP expression in response to 1,25(OH)₂D₃. In-depth analyses on HL-60 cells revealed a rapid and transient increase in TXNIP mRNA levels by 1,25(OH)₂D₃ (3–24 h), followed by a clear reduction at later time points. Furthermore, a strong induction in protein levels was observed only after 96 h of 1,25(OH)₂D₃ treatment. Induction of TXNIP expression by 1,25(OH)₂D₃ was found to be dependent on the availability of glucose in the culture medium, as well as the presence of a functional glucose transport system, indicating an inter-dependence of 1,25(OH)₂D₃ actions and glucose-sensing mechanisms. Moreover, the inhibition of de novo protein synthesis by cycloheximide reduced TXNIP half-life in 24 h, but not in 96 h-1,25(OH)₂D₃-treated HL-60 cells, demonstrating a possible influence of 1,25(OH)₂D₃ on TXNIP stability in long-term treatment.

1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], the bioactive form of vitamin D, has been shown to possess significant anti-tumor potential. While most studies so far have focused on the ability of this molecule to influence the proliferation and apoptosis of cancer cells, more recent data indicate that 1,25(OH)₂D₃ also impacts energy utilization in tumor cells. In this article, we summarize and review the evidence that demonstrates the targeting of metabolic aberrations in cancers by 1,25(OH)₂D₃, and highlight potential mechanisms through which these effects may be executed. We shed light on the ability of this molecule to regulate metabolism-related tumor suppressors and oncogenes, energy- and nutrient-sensing pathways, as well as cell death and survival mechanisms such as autophagy.