Inhibition of endogenous hydrogen sulfide production in clear-cell renal cell carcinoma cell lines and xenografts restricts their growth, survival and angiogenic potential (original) (raw)
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Molecular Functions of Hydrogen Sulfide in Cancer
Pathophysiology, 2021
Hydrogen sulfide (H2S) is a gasotransmitter that exerts a multitude of functions in both physiologic and pathophysiologic processes. H2S-synthesizing enzymes are increased in a variety of human malignancies, including colon, prostate, breast, renal, urothelial, ovarian, oral squamous cell, and thyroid cancers. In cancer, H2S promotes tumor growth, cellular and mitochondrial bioenergetics, migration, invasion, angiogenesis, tumor blood flow, metastasis, epithelia–mesenchymal transition, DNA repair, protein sulfhydration, and chemotherapy resistance Additionally, in some malignancies, increased H2S-synthesizing enzyme expression correlates with a worse prognosis and a higher tumor stage. Here we review the role of H2S in cancer, with an emphasis on the molecular mechanisms by which H2S promotes cancer development, progression, dedifferentiation, and metastasis.
Hydrogen sulfide is an endogenous stimulator of angiogenesis
Proceedings of the National Academy of Sciences, 2009
this process. When CAMs were treated with H 2S biosynthesis inhibitors dl-propylargylglycine or beta-cyano-L-alanine, a reduction in vessel length and branching was observed, indicating that H 2S serves as an endogenous stimulator of the angiogenic response. Stimulation of ECs with vascular endothelial growth factor (VEGF) increased H 2S release, while pharmacological inhibition of H2S production or KATP channels or silencing of cystathionine gamma-lyase (CSE) attenuated VEGF signaling and migration of ECs. These results implicate endothelial H2S synthesis in the pro-angiogenic action of VEGF. Aortic rings isolated from CSE knockout mice exhibited markedly reduced microvessel formation in response to VEGF when compared to wild-type littermates. Finally, in vivo, topical administration of H2S enhanced wound healing in a rat model, while wound healing was delayed in CSE ؊/؊ mice. We conclude that endogenous and exogenous H 2S stimulates EC-related angiogenic properties through a K ATP channel/MAPK pathway.
The Therapeutic Potential of Cystathionine β-Synthetase/Hydrogen Sulfide Inhibition in Cancer
Antioxidants & Redox Signaling, 2015
Significance: Cancer represents a major socioeconomic problem; there is a significant need for novel therapeutic approaches targeting tumor-specific pathways. Recent Advances: In colorectal and ovarian cancers, an increase in the intratumor production of hydrogen sulfide (H 2 S) from cystathionine b-synthase (CBS) plays an important role in promoting the cellular bioenergetics, proliferation, and migration of cancer cells. It also stimulates peritumor angiogenesis inhibition or genetic silencing of CBS exerts antitumor effects both in vitro and in vivo, and potentiates the antitumor efficacy of anticancer therapeutics. Critical Issues: Recently published studies are reviewed, implicating CBS overexpression and H 2 S overproduction in tumor cells as a tumorgrowth promoting ''bioenergetic fuel'' and ''survival factor,'' followed by an overview of the experimental evidence demonstrating the anticancer effect of CBS inhibition. Next, the current state of the art of pharmacological CBS inhibitors is reviewed, with special reference to the complex pharmacological actions of aminooxyacetic acid. Finally, new experimental evidence is presented to reconcile a controversy in the literature regarding the effects of H 2 S donor on cancer cell proliferation and survival. Future Directions: From a basic science standpoint, future directions in the field include the delineation of the molecular mechanism of CBS upregulation of cancer cells and the delineation of the interactions of H 2 S with other intracellular pathways of cancer cell metabolism and proliferation. From the translational science standpoint, future directions include the translation of the recently emerging roles of H 2 S in cancer into human diagnostic and therapeutic approaches. Antioxid. Redox Signal. 22, 424-448. Biological Effects of H 2 S with Relevance for Cancer Biology H 2 S, as a vasodilator and pro-angiogenic mediator Vasorelaxation is one of the first recognized biological effects of H 2 S. Often compared with NO, H 2 S exerts a concentration-dependent vasodilatory effect in blood vessels. The mechanisms of H 2 S-mediated vasodilation include the activation of K ATP channels, a variety of other channels, inhibition of phosphodiesterases, and a synergy with NO (132).
Hydrogen Sulfide: Emerging Role in Bladder, Kidney, and Prostate Malignancies
Oxidative Medicine and Cellular Longevity
Hydrogen sulfide (H2S) is the latest member of the gasotransmitter family and known to play essential roles in cancer pathophysiology. H2S is produced endogenously and can be administered exogenously. Recent studies showed that H2S in cancers has both pro- and antitumor roles. Understanding the difference in the expression and localization of tissue-specific H2S-producing enzymes in healthy and cancer tissues allows us to develop tools for cancer diagnosis and treatment. Urological malignancies are some of the most common cancers in both men and women, and their early detection is vital since advanced cancers are recurrent, metastatic, and often resistant to treatment. This review summarizes the roles of H2S in cancer and looks at current studies investigating H2S activity and expression of H2S-producing enzymes in urinary cancers. We specifically focused on urothelial carcinoma, renal cell carcinoma, and prostate cancer, as they form the majority of newly diagnosed urinary cancers....
In Vivo, 2020
Background: Renal cell carcinoma (RCC) is the most common cancer of the kidney. The most common histotype is clear-cell (cc) RCC. Hydrogen sulfide (H 2 S) is an angiogenic and anti-apoptotic gasotransmitter that is elevated under pseudohypoxic conditions. H 2 S is endogenously produced by three enzymes: Cystathionine γ-lyase (CSE), cystathionine βsynthase (CBS), and 3-mercaptopyruvate sulfurtransferase (MPST). Seeing as increased expression of these enzymes has been observed in other human cancer types, this study aimed to quantify H 2 S-producing enzyme expression in human RCC samples and evaluate whether it correlated with clinical outcomes. Patients and Methods: Eighty-eight human kidney tissue specimens, with healthy and cancerous tissue components, were immunohistochemically stained for CSE, CBS, and MPST. The mean pixel intensity of positively stained areas was quantified. A retrospective analysis was conducted to obtain patient demographics, rates of metastasis/recurrence, and prognostic characteristics. Statistical correlations between enzyme expressions and subsequent patient outcomes were evaluated. Results: There was significantly greater expression of CSE, CBS, and MPST in cc-RCC compared to paired healthy tissue (p<0.0001). The difference in expression of CSE in cancerous versus normal tissue was significantly greater than that for CBS and MPST (p<0.0001 and p<0.01, respectively). Enzyme expression patterns in cancerous versus normal tissue did not correlate with nuclear grade, stage, histological type or cancer recurrence/metastasis. Conclusion: To our knowledge, this is the first report of the differential increase in expression of CSE, CBS, and MPST in human RCC. Although these patterns do not appear to correlate with cancer recurrence, metastasis, size or nuclear grade, their differential increase suggests a potential therapeutic target. Renal cell carcinoma (RCC) is the most common cancer of the kidney. It accounts for 80-90% of all kidney cancer cases and has a cancer-specific mortality rate of 30-40% (1, 2). Incidence rates of RCC have increased over the past few decades, and this is largely attributed to increased detection by diagnostic tools (1, 3). RCC is subdivided into various histotypes based on tumour morphology, genetic signature, clinical manifestation, and area of the nephron where the tumour is present. The most common type of RCC is clearcell (cc) RCC, accounting for 80% of all cases. Other types included papillary, chromophobe and others, which can be classified as non-cc-RCC (4).
Hydrogen sulfide donors and inhibitors in cancer research: A state-of-the-art review
Gene & Protein in Disease
Hydrogen sulfide (H2S), a gaseous biomolecule, is considered a key player in the regulation of various essential cellular events. Normal physiology is determined by the level of endogenous H2S. Any alterations (upregulation and downregulation) to the level of endogenous H2S may lead to illness, including the onset of tumorigenesis. Over the past two decades, extensive research on the role of H2S in cancer development has affirmed the potential pharmacological means to suppress cancer progression by either inhibiting H2S synthesis in cells or exposing exogenously supplied H2S donors to treat different cancers. Some H2S donors and inhibitors release H2S or affect its synthesis. As a result, they have progressed through the development process into widespread clinical use and become increasingly important. The present study draws a detailed discussion on the types of H2S donors and inhibitors and their role in cancer research. We believe that this state-of-the-art review will empower t...
Proceedings of the National Academy of Sciences of the United States of America, 2013
The physiological functions of hydrogen sulfide (H2S) include vasorelaxation, stimulation of cellular bioenergetics, and promotion of angiogenesis. Analysis of human colon cancer biopsies and patient-matched normal margin mucosa revealed the selective up-regulation of the H2S-producing enzyme cystathionine-β-synthase (CBS) in colon cancer, resulting in an increased rate of H2S production. Similarly, colon cancer-derived epithelial cell lines (HCT116, HT-29, LoVo) exhibited selective CBS up-regulation and increased H2S production, compared with the nonmalignant colonic mucosa cells, NCM356. CBS localized to the cytosol, as well as the mitochondrial outer membrane. ShRNA-mediated silencing of CBS or its pharmacological inhibition with aminooxyacetic acid reduced HCT116 cell proliferation, migration, and invasion; reduced endothelial cell migration in tumor/endothelial cell cocultures; and suppressed mitochondrial function (oxygen consumption, ATP turnover, and respiratory reserve capa...
Scientific Reports, 2016
Therapeutic manipulation of the gasotransmitter hydrogen sulfide (H 2 S) has recently been proposed as a novel targeted anticancer approach. Here we show that human lung adenocarcinoma tissue expresses high levels of hydrogen sulfide (H 2 S) producing enzymes, namely, cystathionine beta-synthase (CBS), cystathionine gamma lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST), in comparison to adjacent lung tissue. In cultured lung adenocarcinoma but not in normal lung epithelial cells elevated H 2 S stimulates mitochondrial DNA repair through sulfhydration of EXOG, which, in turn, promotes mitochondrial DNA repair complex assembly, thereby enhancing mitochondrial DNA repair capacity. In addition, inhibition of H 2 S-producing enzymes suppresses critical bioenergetics parameters in lung adenocarcinoma cells. Together, inhibition of H 2 S-producing enzymes sensitize lung adenocarcinoma cells to chemotherapeutic agents via induction of mitochondrial dysfunction as shown in in vitro and in vivo models, suggesting a novel mechanism to overcome tumor chemoresistance. H 2 S is produced in mammalian cells by three distinct enzymes, cystathionine beta-synthase (CBS), cystathionine gamma lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST); during methionine/transsulfuration pathway 1-3. Deregulation of either H 2 S production and/or its downstream actions have been implicated in the pathophysiology of several diseases, including cardiovascular disease, shock, inflammation, diabetes, metabolic syndromes and neurodegeneration 4-11. In connection with cancer, we have previously showed a marked increase in the expression of CBS in colorectal cancer cells (compared to the surrounding normal mucosal margin), which was also recapitulated in multiple colon cancer cell lines 12. ShRNA-mediated silencing, as well as pharmacological inhibition of CBS caused a significant inhibition of the proliferation of colon cancer cells in vitro and in vivo (in tumor-bearing nude mice). Also, silencing or inhibition of CBS suppressed cellular bioenergetics of the colon cancer cells 12. The importance of the CBS/H 2 S in the promotion of cell proliferation and cellular bioenergetics has subsequently been confirmed in ovarian cancer 13 and breast cancer 14. H 2 S generated by overexpressed CSE, has been implicated in melanoma 15. In addition a rapidly increasing body of literature implicates the endogenously generated H 2 S to vascular relaxation and angiogenesis, cell proliferation, mitochondrial function, and cell
Hypoxia and hydrogen sulfide differentially affect normal and tumor-derived vascular endothelium
Redox Biology
Background: endothelial cells play a key role in vessels formation both under physiological and pathological conditions. Their behavior is influenced by blood components including gasotransmitters (H 2 S, NO and CO). Tumor cells are subjected to a cyclic shift between pro-oxidative and hypoxic state and, in this scenario, H 2 S can be both cytoprotective and detrimental depending on its concentration. H 2 S effects on tumors onset and development is scarcely studied, particularly concerning tumor angiogenesis. We previously demonstrated that H 2 S is proangiogenic for tumoral but not for normal endothelium and this may represent a target for antiangiogenic therapeutical strategies. Methods: in this work, we investigate cell viability, migration and tubulogenesis on human EC derived from two different tumors, breast and renal carcinoma (BTEC and RTEC), compared to normal microvascular endothelium (HMEC) under oxidative stress, hypoxia and treatment with exogenous H 2 S. Results: all EC types are similarly sensitive to oxidative stress induced by hydrogen peroxide; chemical hypoxia differentially affects endothelial viability, that results unaltered by real hypoxia. H 2 S neither affects cell viability nor prevents hypoxia and H 2 O 2-induced damage. Endothelial migration is enhanced by hypoxia, while tubulogenesis is inhibited for all EC types. H 2 S acts differentially on EC migration and tubulogenesis. Conclusions: these data provide evidence for a great variability of normal and altered endothelium in response to the environmental conditions.