Hydrogen Sulfide, a Gaseous Transmitter, Stimulates Proliferation of Interstitial Cells of Cajal via Phosphorylation of AKT Protein Kinase

Huang, Ying; Li, Fan; Tong, Weidong; Zhang, Anping; He, Yonghong; Fu, Tao; Liu, Baohua

doi:10.1620/tjem.221.125

Cited by 23 publications

(16 citation statements)

References 40 publications

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“…Thus, the sulfhydration of these proteins may tune and control the oocyte maturation processes. In somatic cells, H 2 S-stimulation of signal pathways of cAMP/PKA [32] and PI3K/Akt [31] was observed. The important contribution these signal pathways make to kinase activity control during mammalian oocyte maturation is known [10], [41].…”

Section: Discussionmentioning

confidence: 99%

“…It is known that H 2 S can influence the activity of various factors including kinases by their direct sulfhydration [39], but no direct effect of H 2 S on MPF and MAPK activities has been yet reported. In addition to possible direct regulation, H 2 S may act indirectly on kinase activity by modifying other molecules, such as ion channels [40], and/or through regulation of up-stream kinases [30], [31]. Thus, the sulfhydration of these proteins may tune and control the oocyte maturation processes.…”

Section: Discussionmentioning

confidence: 99%

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Dual Effects of Hydrogen Sulfide Donor on Meiosis and Cumulus Expansion of Porcine Cumulus-Oocyte Complexes

Nevoral¹,

Petr²,

Gelaude³

et al. 2014

PLoS ONE

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Hydrogen sulfide (H2S) has been revealed to be a signal molecule with second messenger action in the somatic cells of many tissues, including the reproductive tract. The aim of this study was to address how exogenous H2S acts on the meiotic maturation of porcine oocytes, including key maturation factors such as MPF and MAPK, and cumulus expansion intensity of cumulus-oocyte complexes. We observed that the H2S donor, Na2S, accelerated oocyte in vitro maturation in a dose-dependent manner, following an increase of MPF activity around germinal vesicle breakdown. Concurrently, the H2S donor affected cumulus expansion, monitored by hyaluronic acid production. Our results suggest that the H2S donor influences oocyte maturation and thus also participates in the regulation of cumulus expansion. The exogenous H2S donor apparently affects key signal pathways of oocyte maturation and cumulus expansion, resulting in faster oocyte maturation with little need of cumulus expansion.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Dual Effects of Hydrogen Sulfide Donor on Meiosis and Cumulus Expansion of Porcine Cumulus-Oocyte Complexes

Nevoral¹,

Petr²,

Gelaude³

et al. 2014

PLoS ONE

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“…Several lines of studies show that exogenously administered or endogenously produced H 2 S can induce pro-proliferative signaling pathways (including MAP kinases, Akt, ERK1 activation) (5)(6)(7)(35)(36)(37)(38)(39)(40)(41)(42)(43). By inhibiting colon cancer cell H 2 S production, YD0171 may suppress these signaling processes, although this remains to be directly investigated in future studies.…”

Section: Discussionmentioning

confidence: 99%

Cystathionine-β-Synthase Inhibition for Colon Cancer: Enhancement of the Efficacy of Aminooxyacetic Acid via the Prodrug Approach

Chao

Zatarain

Ding

et al. 2016

Mol Med

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Colon cancer cells contain high levels of cystathionine-β-synthase (CBS). Its product, hydrogen sulfide (H 2 S), promotes the growth and proliferation of colorectal tumor cells. To improve the antitumor efficacy of the prototypical CBS inhibitor aminooxyacetic acid (AOAA), we have designed and synthesized YD0171, a methyl ester derivative of AOAA. The antiproliferative effect of YD0171 exceeded the antiproliferative potency of AOAA in HCT116 human colon cancer cells. The esterase inhibitor paraoxon prevented the cellular inhibition of CBS activity by YD0171. YD0171 suppressed mitochondrial respiration and glycolytic function and induced G0/G1 arrest, but did not induce tumor cell apoptosis or necrosis. Metabolomic analysis in HCT116 cells showed that YD0171 affects multiple pathways of cell metabolism. The efficacy of YD0171 as an inhibitor of tumor growth was also tested in nude mice bearing subcutaneous HCT116 cancer cell xenografts. Animals were treated via subcutaneous injection of vehicle or AOAA (0.1, 0.5 or 1 mg/kg/d) for 3 wks. Tumor growth was significantly reduced by 9 mg/kg/d AOAA, but not at the lower doses. YD0171 was more potent: tumor volume was significantly inhibited at 0.5 and 1 mg/kg/d. Thus, the in vivo efficacy of YD0171 is nine times higher than that of AOAA. YD0171 (1 mg/kg/d) attenuated tumor growth and metastasis formation in the intracecal HCT116 tumor model. YD0171 (3 mg/kg/d) also reduced tumor growth in patient-derived tumor xenograft bearing athymic mice. YD0171 (3 mg/kg/d) induced the regression of established HCT116 tumors in vivo. A 5-d safety study in mice demonstrated that YD0171 at 20 mg/kg/d (given in two divided doses) does not increase plasma markers of organ injury, nor does it induce histological alterations in the liver or kidney. YD0171 caused a slight elevation in plasma homocysteine levels. In conclusion, the prodrug approach improves the pharmacological profile of AOAA; YD0171 represents a prototype for CBS inhibitory anticancer prodrugs. By targeting colorectal cancer bioenergetics, an emerging important hallmark of cancer, the approach exemplified herein may offer direct translational opportunities.

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“…Several lines of evidence from recent studies demonstrate significant increases in exhaled H 2 S levels in cancer patients (4,48,66,140); however, the identification of its biological source was not investigated. In addition, elevated urinary thiosulfate (the stable breakdown product of H 2 S) levels were found in prostate cancer patients; the mean thiosulfate levels in prostate cancer patients were almost 50 times higher than in the control groups and 5 times higher than in patients with benign prostatic hyperplasia (19).…”

Section: Increased Expression Of Cbs And/or Increased Production Of Hmentioning

confidence: 99%

The Therapeutic Potential of Cystathionine β-Synthetase/Hydrogen Sulfide Inhibition in Cancer

Hellmich

Coletta

Chao

et al. 2015

Antioxidants & Redox Signaling

208

186

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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,

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Hydrogen Sulfide, a Gaseous Transmitter, Stimulates Proliferation of Interstitial Cells of Cajal via Phosphorylation of AKT Protein Kinase

Cited by 23 publications

References 40 publications

Dual Effects of Hydrogen Sulfide Donor on Meiosis and Cumulus Expansion of Porcine Cumulus-Oocyte Complexes

Dual Effects of Hydrogen Sulfide Donor on Meiosis and Cumulus Expansion of Porcine Cumulus-Oocyte Complexes

Cystathionine-β-Synthase Inhibition for Colon Cancer: Enhancement of the Efficacy of Aminooxyacetic Acid via the Prodrug Approach

The Therapeutic Potential of Cystathionine β-Synthetase/Hydrogen Sulfide Inhibition in Cancer

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