Steroid biosynthesis

About: Steroid biosynthesis is a research topic. Over the lifetime, 1721 publications have been published within this topic receiving 58977 citations.

Intracrine Androgens and AKR1C3 Activation Confer Resistance to Enzalutamide in Prostate Cancer

Abstract: The introduction of enzalutamide and abiraterone has led to improvement in the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, acquired resistance to enzalutamide and abiraterone therapies frequently develops within a short period in many patients. In the present study, we developed enzalutamide resistant prostate cancer cells in an effort to understand the mechanisms of resistance. Global gene expression analysis showed that steroid biosynthesis pathway is activated in enzalutamide resistant prostate cancer cells. One of the crucial steroidogenic enzymes, AKR1C3, was significantly elevated in enzalutamide resistant cells. In addition, AKR1C3 is highly expressed in metastatic and recurrent prostate cancer and in enzalutamide resistant prostate xenograft tumors. Liquid Chromatography-Mass Spectrometry (LC-MS) analysis of the steroid metabolites revealed that androgen precursors such as cholesterol, DHEA and progesterone, as well as androgens are highly up regulated in enzalutamide resistant prostate cancer cells compared to the parental cells. Knock down of AKR1C3 expression by shRNA or inhibition of AKR1C3 enzymatic activity by indomethacin resensitized enzalutamide resistant prostate cancer cells to enzalutamide treatment both in vitro and in vivo. In contrast, overexpression of AKR1C3 confers resistance to enzalutamide. Furthermore, the combination of indomethacin and enzalutamide resulted in significant inhibition of enzalutamide-resistant tumor growth. These results suggest that AKR1C3 activation is a critical resistance mechanism associated with enzalutamide resistance, targeting intracrine androgens and AKR1C3 will overcome enzalutamide resistance and improve survival of advanced prostate cancer patients.

Comprehensive analysis of β-catenin target genes in colorectal carcinoma cell lines with deregulated Wnt/β-catenin signaling

Abstract: Deregulation of Wnt/β-catenin signaling is a hallmark of the majority of sporadic forms of colorectal cancer and results in increased stability of the protein β-catenin. β-catenin is then shuttled into the nucleus where it activates the transcription of its target genes, including the proto-oncogenes MYC and CCND1 as well as the genes encoding the basic helix-loop-helix (bHLH) proteins ASCL2 and ITF-2B. To identify genes commonly regulated by β-catenin in colorectal cancer cell lines, we analyzed β-catenin target gene expression in two non-isogenic cell lines, DLD1 and SW480, using DNA microarrays and compared these genes to β-catenin target genes published in the PubMed database and DNA microarray data presented in the Gene Expression Omnibus (GEO) database. Treatment of DLD1 and SW480 cells with β-catenin siRNA resulted in differential expression of 1501 and 2389 genes, respectively. 335 of these genes were regulated in the same direction in both cell lines. Comparison of these data with published β-catenin target genes for the colon carcinoma cell line LS174T revealed 193 genes that are regulated similarly in all three cell lines. The overlapping gene set includes confirmed β-catenin target genes like AXIN2, MYC, and ASCL2. We also identified 11 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways that are regulated similarly in DLD1 and SW480 cells and one pathway – the steroid biosynthesis pathway – was regulated in all three cell lines. Based on the large number of potential β-catenin target genes found to be similarly regulated in DLD1, SW480 and LS174T cells as well as the large overlap with confirmed β-catenin target genes, we conclude that DLD1 and SW480 colon carcinoma cell lines are suitable model systems to study Wnt/β-catenin signaling and associated colorectal carcinogenesis. Furthermore, the confirmed and the newly identified potential β-catenin target genes are useful starting points for further studies.

Steroid hormone receptors: evolution, ligands, and molecular basis of biologic function.

Abstract: The characterization of the superfamily of nuclear receptors, in particular the steroid/retinoid/thyroid hormone receptors, has resulted in a more complete understanding of how a repertoire of hormonally and nutritionally derived lipophilic ligands controls cell functions to effect development and homeostasis. As transducers of hormonal signaling in the nucleus, this superfamily of DNA-binding proteins appears to represent a crucial link in the emergence of multicellular organisms. Because nuclear receptors bind and are conformationally activated by a chemically diverse array of ligands, yet are closely related in general structure, they present an intriguing example of paralogous evolution. It is hypothesized that an ancient prototype receptor evolved into an intricate set of dimerizing isoforms, capable of recognizing an ensemble of hormone-responsive element motifs in DNA, and exerting ligand-directed combinatorial control of gene expression. The effector domains of nuclear receptors mediate transcriptional activation by recruiting coregulatory multisubunit complexes that remodel chromatin, target the initiation site, and stabilize the RNA polymerase II machinery for repeated rounds of transcription of the regulated gene. Because some nuclear receptors also function in gene repression, while others are constitutive activators, this superfamily of proteins provides a number of avenues for investigating hormonal regulation of gene expression. This review surveys briefly the latest findings in the nuclear receptor field and identifies particular areas where future studies should be fruitful. J. Cell. Biochem. Suppls. 32/33:110-122, 1999.

Vitamin a, carotenoids and cell function

Abstract: Summary I. Both deficiency and excess of vitamin A produce many diverse pathological changes. Lipoprotein membranes have recently been found to be concerned in a number of the actions of excess of the vitamin. This article is devoted principally to a discussion of the interactions and possible functions of vitamin A within membranes, both in hypervitaminosis and under physiological conditions. 2. Excess of vitamin A. (a) As a result of its amphipathic molecular structure, retinol is highly surface active. (b) The initial action of excess of retinol on erythrocytes is an expansion of the cell membrane; this is followed by haemolysis unless the cells are kept cold, or inhibitors, such as vitamin E, are present. (c) Addition of retinol to fibroblasts growing in vitro causes degranulation and swelling of the endoplasmic reticulum, swelling of Golgi vacuoles and mitochondria, and the formation of cytolysomes. (d) Isolated mitochondria from certain tissues also swell in the presence of retinol. This swelling is apparently not dependent on respiration, but is inhibited by vitamin E. (e) Lysosomal enzymes are released by excess of retinol, both in vivo and in vitro. A number of the effects of excess vitamin A on connective tissues may be ascribed to this action; these effects are inhibited by hydrocortisone, which stabilizes lysosomes, but are not significantly inhibited by vitamin E. (f) Closely related, but physiologically inactive, derivatives of retinol are relatively inactive towards membranes; membranes might therefore also be concerned in the physiological functions of retinol. (g) Vitamin A has recently been shown to have marked effects on the membranes of certain bacteria and viruses. 3. Deficiency of vitamin A. (a) The diminished synthesis of mucopolysaccharide observed in deficiency may result from an interference with the synthesis of ‘active sulphate’ but, in view of conflicting observations, this cannot be considered as proven. (b) Suggestions have been made that lipoprotein membranes may be concerned in the actions of vitamin A on both mucopolysaccharide and steroid biosynthesis. (c) The action of the vitamin in biological oxidations is far from clear. Recently it has been found that deficiency increases, and excess of vitamin A decreases, the oxidation of succinate by homogenates of rat liver. (d) Organ culture experiments indicate that vitamin A acts directly on mouse prostate glands to prevent the squamous changes that are characteristic of deficiency. 4. A conjugated chain of alternating single and double bonds is a chemical feature common to vitamin A and the carotenoids. (a) Such a chain is characterized by a high electron mobility; this has been studied both theoretically and experimentally in relation to electron transfer in photosynthesis, to ion transport, and to super-conduction and semi-conduction in biological systems. (b) The role of vitamin A in vision may be an evolutionary development of the function of the carotenoids in photosynthesis. In the eye, retinal is intimately concerned with the structure and function of lipoprotein membranes. We have suggested that changes in electron mobility may be functionally associated with the isomerization of 11-CM retinal by light. (c) Vitamin A, or carotenoids, may be concerned in the receptor systems of olfaction and taste. (d) Photosynthesis in chloroplasts has many structural, chemical and functional features in common with respiration in mitochondria. Carotenoids are found in ox-heart mitochondria but the presence of vitamin A is uncertain. (e) We have suggested that vitamin A or a metabolite retaining the conjugated chain may be present under physiological conditions in the lipids of biological membranes and that, by virtue of its mobile electrons, it may function in mitochondrial electron transport. 5. Active forms of vitamin A. (a) Recent work indicates that retinoic acid, or a metabolite of retinoic acid, may be the active form. It has not been established conclusively, however, that retinoic acid is normally formed in vivo from retinol. (b) It is conceivable that, if vitamin A is concerned in electron transfer, the vitamin may penetrate lipoprotein membranes as retinol and that it may subsequently be converted to a functional derivative. In this way, the membranes of animal cells may receive the carotenoid skeleton which, unlike plant and bacterial cells, they cannot synthesize for themselves. We are most grateful to Dame Honor Fell, F.R.S., Sir Rudolph Peters, F.R.S., and Miss Audrey M. Glauert for reading the manuscript of this article and for their helpful suggestions. We thank Mr R. A. Parker and Mr I. Armond for preparing the plates and figures, and Mrs M. Wright for her careful typing.