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Review Article Hydrogen Sulfide Signaling Axis As a Target for Prostate Cancer Therapeutics

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Review Article Hydrogen Sulfide Signaling Axis As a Target for Prostate Cancer Therapeutics Hindawi Publishing Corporation Prostate Cancer Volume 2016, Article ID 8108549, 9 pages http://dx.doi.org/10.1155/2016/8108549 Review Article Hydrogen Sulfide Signaling Axis as a Target for Prostate Cancer Therapeutics Mingzhe Liu,1 Lingyun Wu,1,2 Sabine Montaut,3 and Guangdong Yang3 1 Cardiovascular and Metabolic Research Unit, Lakehead University, Thunder Bay, ON, Canada P7B 5E1 2Department of Health Sciences, Lakehead University, Thunder Bay, ON, Canada P7B 5E1 3Department of Chemistry and Biochemistry, Laurentian University, Sudbury, ON, Canada P3E 2C6 Correspondence should be addressed to Guangdong Yang; [email protected] Received 19 October 2015; Accepted 28 January 2016 Academic Editor: David Nanus Copyright © 2016 Mingzhe Liu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Hydrogen sulfide (H2S) was originally considered toxic at elevated levels; however just in the past decade H2Shasbeenproposed to be an important gasotransmitter with various physiological and pathophysiological roles in the body. H2Scanbegenerated endogenously from L-cysteine by multiple enzymes, including cystathionine gamma-lyase, cystathionine beta-synthase, and 3- mercaptopyruvate sulfurtransferase in combination with cysteine aminotransferase. Prostate cancer is a major health concern and no effective treatment for prostate cancers is available.2 H S has been shown to inhibit cell survival of androgen-independent, androgen-dependent, and antiandrogen-resistant prostate cancer cells through different mechanisms. Various2 H S-releasing compounds, including sulfide salts, diallyl ulfide,dis diallyl trisulfide, sulforaphane, and other polysulfides, also have been shown to inhibit prostate cancer growth and metastasis. The expression of H2S-producing enzyme was reduced in both human prostate cancer tissues and prostate cancer cells. Androgen receptor (AR) signaling is indispensable for the development of castration resistant prostate cancer, and H2S was shown to inhibit AR transactivation and contributes to antiandrogen-resistant status. In this review, we summarized the current knowledge of H2S signaling in prostate cancer and described the molecular alterations, which may bring this gasotransmitter into the clinic in the near future for developing novel pharmacological and therapeutic interventions for prostate cancer. 1. Introduction is an endothelial-derived relaxing factor and acts as a sig- naling molecule in the cardiovascular system. We now know Hydrogen sulfide (H2S) is a colorless, flammable gas with that NO is the first identified gasotransmitter. Similar to NO, the characteristic odor of rotten eggs. H2Sistraditionally H2S possesses all the criteria to qualify as a gasotransmitter considered as a toxic environmental pollutant with little or [4, 6]. First, H2S is a small gas with the simple molecular no physiological significance. The mechanism of H2Stoxicity structure of two hydrogen atoms and one sulfide atom. is thought to bind and inhibit mitochondrial cytochrome oxidase, which is involved in cellular oxidative processes Secondly, H2S has higher lipid solubility and can penetrate and energy production [1]. The inhibition of cytochrome easily through cell membranes without using any specific oxidase blocks the electron transport chain, decreases ATP transporter/receptor. Thirdly, H2Snotonlyisfoundfrom production, and finally induces cell death. However, just the environment, but also can be endogenously generated in the last decade, H2S is acknowledged to be one impor- in almost all organs and cells by specific enzymes through tant gasotransmitter, influencing plentiful physiological and reverse-transsulfuration pathway. Fourthly, H2S generates pathological processes [2–6]. In 1998, three Nobel winners in various functions at physiologically relevant concentrations Medicine and Physiology, Drs. Robert F. Furchgott, Louis J. by targeting at specific cellular and molecular sites, which can Ignarro, and Ferid Murad, discovered that nitric oxide (NO) be mimicked by exogenously applied H2S donors. 2 Prostate Cancer O Production HS OH O NH2 Homocysteine HO OH CBS NH2 O NH2 Serine O HO S NH2 OH Cystathionine CSE O O H HS OH + OH + N O CAT NH2 O H H Cysteine HS -Ketobutyrate Ammonia OH CSE CBS O O H 3-Mercaptopyruvate H2S + OH + N MPST O H H Pyruvate Ammonia Functions Metabolism/degradation Relaxing blood vessels Helping memory Oxidation sulfate Methylation CH3SH Energy generation Metabolism Scavenge methemoglobin/hemin Breakdown SQR/rhodanese Inflammation Cell survival and death Storage bound sulfane sulfur Figure 1: H2S biosynthesis, functions, and metabolism. So let us first look at how H2S is endogenously produced. In mammalian cells, H2S can be endogenously produced through the transsulfuration pathway. With cysteine as the main substrate, CBS or CSE, which we called cystathionine gamma-lyase or cystathionine beta-synthase, can catalyze cysteine into H2S and other products. The expression of CBS and CSE is tissue-specific, CBS is mostly expressed in brain, and CSE is in the cardiovascular system and other big tissues, such as liver and kidney. The half-life of H2S inside the cells is very fast; it is estimated in several seconds and can be quickly oxidized, scavenged, or broken down by different ways. Now it has been widely recognized that H2S plays very important physiological role in the whole body and also cells; for example, it can relax blood vessel and acts as an endothelial deprived hyperpolarizing factor, can enhance long term potentiation and help memory, and can control energy generation and regulate metabolism, inflammation; more importantly, H2S is required for cell fate decision; that is the topic we are going to talk about in the following. H2S is involved in an array of cellular signals regulating with the sulfhydryl group of cysteine forming persulhydral cardiac, neurological, and respiratory functions, as well as group (–SSH), termed as protein S-sulfhydration [9–13]. It is cellular metabolism and survival [5, 7]. Many diseases includ- predicted that S-sulfhydration changes protein structure and ing cardiovascular diseases, neurological diseases, shock, alters protein activity and functions. The modified cysteine sepsis, metabolic disorders, and cancers have been linked to residueishighlyreactiveandusuallyincreasesthecatalytic abnormal endogenous H2Sfunctionsandmetabolism[4]. activity of targeted proteins [14]. Although H2S has numerous physiological functions, the actual levels of H2S present in biological tissues and fluids 2. H2S Biosynthesis and Metabolism are not really known. The past studies have shown that the concentration of H2S in circulation ranged from nanomolar Now it is recognized that endogenous H2S generation is to micromolar one depending on different detection methods from enzymatic and nonenzymatic pathways [4, 5]. At least [2]. H2S usually provides cytoprotective effects at very low 3 enzymes are responsible for endogenous H2S generation concentrations but is cytotoxic at higher concentrations in mammalian cells, including two cytosolic pyridoxal-5 - via free radical and oxidant generation, glutathione (GSH) phosphate-dependent enzymes, cystathionine beta-synthase depletion, and initiation of proapoptotic gene expression (CBS, EC 4.2.1.22) and cystathionine gamma-lyase (CSE, EC [8]. It is proposed that H2Smediatesallthesecellular 4.4.1.1), and a mitochondrial enzyme 3-mercaptopyruvate functions through protein posttranslational modifications. sulfurtransferase (MPST,EC 2.8.1.2) (Figure 1) [5, 8]. All these H2S can modify cysteine residues of the proteins and bind threeenzymesusesulfur-containingaminoacidsL-cysteine Prostate Cancer 3 assubstratetogenerateH2S. CBS catalyzes the condensation LNCaP in comparison with all other cells. In LNCaP cells, of serine and homocysteine to form cystathionine, and CSE both CBS and CSE are located in the cytoplasm as evidenced then cleaves the C--S bond of cystathionine to yield cysteine, by immunostaining, and the CBS/CSE activities parallel the -ketobutyrate, and ammonia (NH3). Moreover, both CBS CBS/CSE protein levels [16]. In contrast, CBS and CSE are and CSE can use cysteine as substrate to produce H2S, hardly detected in the normal prostatic peripheral zone and pyruvate and NH3 are two other byproducts. Cysteine epithelial cell line RWPE-1. Gai et al. further demonstrated aminotransferase (CAT) provides 3-mercaptopyruvate from that not only CBS and CSE but also MPST is present in cysteine for MPST to produce H2S. These enzymes are critical human prostate tissue, and CSE is expressed at much higher for the maintenance of H2S homeostasis by precisely regu- levelincomparisonwithCBSandMPST[17].Incontrast, lating H2S levels in tissues [8]. It is worth noting that MPST Zhao et al. found that MPST is not expressed in both functions more efficiently at very high pH. At physiological human prostate adenocarcinoma and normal prostate tissues condition, the contribution of MPST to endogenous H2S [18]. The difference may be due to the detection method production is negligible in comparison with CBS and CSE and antibody resource. Furthermore, Zhao et al. provided [15]. The expression of these 3 enzymes in the body is tissue- evidence that the expression of CSE but not CBS is signifi- specific. They can be all expressed in one organ, or only one cantly reduced in prostate cancer tissue when
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