LXRs are finally being adequately targeted in atherosclerosis

International audienc

Targeting NR1H/liver X receptor with dendrogenin A differentiates tumor cells to activate a new secretory pathway releasing immunogenic anti-tumor vesicles enriched in LC3-II-associated exosomes

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Contribution of Sub-Saharan African medicinal plants to cancer research: Scientific basis 2013–2023

Cancer incidence and mortality rates are increasing worldwide. Cancer treatment remains a real challenge for African countries, especially in sub-Saharan Africa where funding and resources are very limited. High costs, side effects and drug resistance associated with cancer treatment have encouraged scientists to invest in research into new herbal cancer drugs. In order to identify potential anticancer plants for drug development, this review aims to collect and summarize anticancer activities (in vitro/in vivo) and molecular mechanisms of sub-Saharan African medicinal plant extracts against cancer cell lines. Scientific databases such as ScienceDirect, Google Scholar and PubMed were used to search for research articles published from January 2013 to May 2023 on anticancer medicinal plants in sub-Saharan Africa. The data were analyzed to highlight the cytotoxicity and molecular mechanisms of action of these listed plants. A total of 85 research papers covering 204 medicinal plant species were selected for this review. These plants come from 57 families, the most dominant being the plants of the family Amaryllidaceae (16), Fabaceae (14), Annonaceae (10), Asteraceae (10). Plant extracts exert their anticancer activity mainly by inducing apoptosis and stopping the cell cycle of cancer cells. Several plant extracts from sub-Saharan Africa therefore have strong potential for the search for original anticancer phytochemicals. Chemoproteomics, multi-omics, genetic editing technology (CRISPR/Cas9), combined therapies and artificial intelligence tools are cutting edge emerging technologies that facilitate the discovery and structural understanding of anticancer molecules of medicinal plants, reveal their direct targets, explore their therapeutic uses and molecular bases

Ethanolic extract of Algerian propolis decreases androgen receptor transcriptional activity in cultured LNCaP cells.

Antiandrogens have a peculiar place in the treatment of metastatic prostate cancer by blocking the androgen receptor (AR). Unfortunately, aggressive tumors could rapidly develop into a castration resistant state. It is therefore essential to look for new molecules that are more effective, affecting not only the androgen signaling and with minimum undesirable effects. Natural products are an interesting source of new therapeutics, especially for cancer therapy as 70% of them have botanical origin. Based on an ethnobotany screening, we evaluated the effects of ethanolic extract of propolis (EEP) from Algeria on LNCaP cells. Results pointed out that EEP reduces the survival of LNCaP cells with an IC50 of 0.04 mg/ml, induces the apoptosis and blocks the cell cycle at G0/G1 phase. Interestingly, EEP decreased the accumulation of AR suggesting some anti-androgen activity. Indeed, secreted amount of the androgen target protein PSA was decreased when LNCaP cells were incubated with EEP, starting after 4 h of treatment. This anti-androgen activity was also shown on the androgen target genes Fkbp5 and Sgk1. Finally, the capacity of EEP to block AR functioning was demonstrated in transient transfections with human AR and the reporter gene ARE-tk-Luc. Propolis antagonizes the induction of the luciferase activity induced by the natural androgen DHT (10(-8)M) or the synthetic AR agonist R1881 (10(-7)M). Altogether, these results highlight the potential pharmacological effects of EEP in future treatments of prostate cancer

New Insights in Prostate Cancer Development and Tumor Therapy: Modulation of Nuclear Receptors and the Specific Role of Liver X Receptors

Prostate cancer (PCa) incidence has been dramatically increasing these last years in westernized countries. Though localized PCa is usually treated by radical prostatectomy, androgen deprivation therapy is preferred in locally advanced disease in combination with chemotherapy. Unfortunately, PCa goes into a castration-resistant state in the vast majority of the cases, leading to questions about the molecular mechanisms involving the steroids and their respective nuclear receptors in this relapse. Interestingly, liver X receptors (LXRα/NR1H3 and LXRβ/NR1H2) have emerged as new actors in prostate physiology, beyond their historical roles of cholesterol sensors. More importantly LXRs have been proposed to be good pharmacological targets in PCa. This rational has been based on numerous experiments performed in PCa cell lines and genetic animal models pointing out that using selective liver X receptor modulators (SLiMs) could actually be a good complementary therapy in patients with a castration resistant PCa. Hence, this review is focused on the interaction among the androgen receptors (AR/NR3C4), estrogen receptors (ERα/NR3A1 and ERβ/NR3A2), and LXRs in prostate homeostasis and their putative pharmacological modulations in parallel to the patients’ support

Sequential Ras/MAPK and PI3K/AKT/mTOR pathways recruitment drives basal extrusion in the prostate-like gland of Drosophila

International audienceOne of the most important but less understood step of epithelial tumourigenesis occurs when cells acquire the ability to leave their epithelial compartment. This phenomenon, described as basal epithelial cell extrusion (basal extrusion), represents the first step of tumour invasion. However, due to lack of adequate in vivo model, implication of emblematic signalling pathways such as Ras/Mitogen-Activated Protein Kinase (MAPK) and phosphoinositide 3 kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signalling pathways , is scarcely described in this phenomenon. We have developed a unique model of basal extrusion in the Drosophila accessory gland. There, we demonstrate that both Ras/MAPK and PI3K/AKT/mTOR pathways are necessary for basal extrusion. Furthermore, as in prostate cancer, we show that these pathways are co-activated. This occurs through set up of Epi-dermal Growth Factor Receptor (EGFR) and Insulin Receptor (InR) dependent autocrine loops, a phenomenon that, considering human data, could be relevant for prostate cancer

Targeting the liver X receptor with dendrogenin A differentiates tumour cells to secrete immunogenic exosome‐enriched vesicles

International audienceTumour cells are characterized by having lost their differentiation state. They constitutively secrete small extracellular vesicles (sEV) called exosomes when they come from late endosomes. Dendrogenin A (DDA) is an endogenous tumour suppressor cholesterol-derived metabolite. It is a new class of ligand of the nuclear Liver X receptors (LXR) which regulate cholesterol homeostasis and immunity. We hypothesized that DDA, which induces tumour cell differentiation, inhibition of tumour growth and immune cell infiltration into tumours, could functionally modify sEV secreted by tumour cells. Here, we have shown that DDA differentiates tumour cells by acting on the LXRβ. This results in an increased production of sEV (DDA-sEV) which includes exosomes. The DDA-sEV secreted from DDA-treated cells were characterized for their content and activity in comparison to sEV secreted from control cells (C-sEV). DDA-sEV were enriched, relatively to C-sEV, in several proteins and lipids such as differentiation antigens, "eat-me" signals, lipidated LC3 and the endosomal phospholipid bis(monoacylglycero)phosphate, which stimulates dendritic cell maturation and a Th1 T lymphocyte polarization. Moreover, DDA-sEV inhibited the growth of tumours implanted into immunocompetent mice compared to control conditions. This study reveals a pharmacological control through a nuclear receptor of exosome-enriched tumour sEV secretion, composition and immune function. Targeting the LXR may be a novel way to reprogram tumour cells and sEV to stimulate immunity against cancer

Absence of nuclear receptors LXRs impairs immune response to androgen deprivation and leads to prostate neoplasia

Chronic inflammation is now a well-known precursor for cancer development. Infectious prostatitis are the most common causes of prostate inflammation, but emerging evidence points the role of metabolic disorders as a potential source of cancer-related inflammation. Although the widely used treatment for prostate cancer based on androgen deprivation therapy (ADT) effectively decreases tumor size, it also causes profound alterations in immune tumor microenvironment within the prostate. Here, we demonstrate that prostates of a mouse model invalidated for nuclear receptors liver X receptors (LXRs), crucial lipid metabolism and inflammation integrators, respond in an unexpected way to androgen deprivation. Indeed, we observed profound alterations in immune cells composition, which was associated with chronic inflammation of the prostate. This was explained by the recruitment of phagocytosis-deficient macrophages leading to aberrant hyporesponse to castration. This phenotypic alteration was sufficient to allow prostatic neoplasia. Altogether, these data suggest that ADT and inflammation resulting from metabolic alterations interact to promote aberrant proliferation of epithelial prostate cells and development of neoplasia. This raises the question of the benefit of ADT for patients with metabolic disorders