Cystathionine Beta-Synthase (CBS) Contributes to Advanced Ovarian Cancer Progression and Drug Resistance
Sanjib Bhattacharyya,Sounik Saha,Karuna Giri,Ian R. Lanza,K. Sreekumar Nair,Nicholas B. Jennings,Cristian Rodriguez-Aguayo,Gabriel Lopez-Berestein,Eati Basal,Amy L. Weaver,Daniel W. Visscher,William A. Cliby,Anil K. Sood,Resham Bhattacharya,Priyabrata Mukherjee +14 more
TLDR
An important role is reported in promoting ovarian tumor growth and maintaining drug resistant phenotype by controlling cellular redox behavior and regulating mitochondrial bioenergetics in ovarian cancer cells.Abstract:
Background
Epithelial ovarian cancer is the leading cause of gynecologic cancer deaths. Most patients respond initially to platinum-based chemotherapy after surgical debulking, however relapse is very common and ultimately platinum resistance emerges. Understanding the mechanism of tumor growth, metastasis and drug resistant relapse will profoundly impact the therapeutic management of ovarian cancer.
Methods/Principal Findings
Using patient tissue microarray (TMA), in vitro and in vivo studies we report a role of of cystathionine-beta-synthase (CBS), a sulfur metabolism enzyme in ovarian carcinoma. We report here that the expression of cystathionine-beta-synthase (CBS), a sulfur metabolism enzyme, is common in primary serous ovarian carcinoma. The in vitro effects of CBS silencing can be reversed by exogenous supplementation with the GSH and H2S producing chemical Na2S. Silencing CBS in a cisplatin resistant orthotopic model in vivo by nanoliposomal delivery of CBS siRNA inhibits tumor growth, reduces nodule formation and sensitizes ovarian cancer cells to cisplatin. The effects were further corroborated by immunohistochemistry that demonstrates a reduction of H&E, Ki-67 and CD31 positive cells in si-RNA treated as compared to scrambled-RNA treated animals. Furthermore, CBS also regulates bioenergetics of ovarian cancer cells by regulating mitochondrial ROS production, oxygen consumption and ATP generation. This study reports an important role of CBS in promoting ovarian tumor growth and maintaining drug resistant phenotype by controlling cellular redox behavior and regulating mitochondrial bioenergetics.
Conclusion
The present investigation highlights CBS as a potential therapeutic target in relapsed and platinum resistant ovarian cancer.read more
Citations
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Gasotransmitters in cancer: from pathophysiology to experimental therapy
TL;DR: The role of each gasotransmitter in cancer and the effects of pharmacological agents — some of which are in early-stage clinical studies — that modulate the levels of eachGasotransmitters are discussed.
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International Union of Basic and Clinical Pharmacology. CII: Pharmacological Modulation of H2S Levels: H2S Donors and H2S Biosynthesis Inhibitors.
TL;DR: The present article overviews the currently known H 2S donors and H2S biosynthesis inhibitors, delineates their mode of action, and offers examples for their biologic effects and potential therapeutic utility.
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A Review of Hydrogen Sulfide Synthesis, Metabolism, and Measurement: Is Modulation of Hydrogen Sulfide a Novel Therapeutic for Cancer?
Xu Cao,Lei Ding,Zhi-Zhong Xie,Yong Yang,Yong Yang,Matthew Whiteman,Philip K. Moore,Jin-Song Bian +7 more
TL;DR: A bell-shaped model has been proposed to explain the role of H2S in cancer development and indicates that inhibition of H1N1 biosynthesis and H1S supplementation serve as two distinct ways for cancer treatment.
Journal ArticleDOI
Amino Acid Restriction Triggers Angiogenesis via GCN2/ATF4 Regulation of VEGF and H2S Production.
Alban Longchamp,Alban Longchamp,Teodelinda Mirabella,Teodelinda Mirabella,Alessandro Arduini,Michael R MacArthur,Abhirup Das,Abhirup Das,J. Humberto Treviño-Villarreal,Christopher Hine,Issam Ben-Sahra,Nelson H. Knudsen,Lear E. Brace,Justin S. Reynolds,Pedro Mejia,Ming Tao,Gaurav Sharma,Rui Wang,Jean-Marc Corpataux,Jacques-Antoine Haefliger,Kyo Han Ahn,Chih-Hao Lee,Brendan D. Manning,David A. Sinclair,David A. Sinclair,Christopher S. Chen,Christopher S. Chen,C. Keith Ozaki,James R. Mitchell +28 more
TL;DR: Sulfur amino acid restriction is identified as a proangiogenic trigger, promoting increased VEGF expression, migration and sprouting in ECs in vitro, and increased capillary density in mouse skeletal muscle in vivo via the GCN2/ATF4 amino acid starvation response pathway independent of hypoxia or HIF1α.
Journal ArticleDOI
The therapeutic potential of cystathionine β-synthetase/hydrogen sulfide inhibition in cancer.
TL;DR: The current state of the art of pharmacological CBS inhibitors is reviewed, with special reference to the complex pharmacological actions of aminooxyacetic acid, and a controversy in the literature regarding the effects of H2S donor on cancer cell proliferation and survival is presented.
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