Cystathionine Beta-Synthase (CBS) Contributes to Advanced Ovarian Cancer Progression and Drug Resistance

被引:213
作者
Bhattacharyya, Sanjib [1 ]
Saha, Sounik [2 ]
Giri, Karuna [1 ]
Lanza, Ian R. [3 ]
Nair, K. Sreekumar [3 ]
Jennings, Nicholas B. [4 ]
Rodriguez-Aguayo, Cristian [5 ]
Lopez-Berestein, Gabriel [5 ,6 ]
Basal, Eati [7 ]
Weaver, Amy L. [8 ]
Visscher, Daniel W. [9 ]
Cliby, William [7 ]
Sood, Anil K. [4 ,5 ,6 ]
Bhattacharya, Resham [10 ]
Mukherjee, Priyabrata [2 ]
机构
[1] Mayo Clin, Coll Med, Dept Biochem & Mol Biol, Rochester, MN USA
[2] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Stephenson Canc Ctr, Oklahoma City, OK USA
[3] Mayo Clin, Coll Med, Div Endocrinol, Rochester, MN USA
[4] Univ Texas Houston, MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA
[5] Univ Texas Houston, MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA
[6] Univ Texas Houston, MD Anderson Canc Ctr, Ctr RNA Interference & Noncoding RNA, Houston, TX 77030 USA
[7] Mayo Clin, Coll Med, Dept Obstet & Gynecol, Rochester, MN USA
[8] Mayo Clin, Coll Med, Dept Biostat & Bioinformat, Rochester, MN USA
[9] Mayo Clin, Coll Med, Dept Pathol, Rochester, MN USA
[10] Univ Oklahoma, Hlth Sci Ctr, Dept Obstet & Gynecol, Stephenson Canc Ctr, Oklahoma City, OK 73190 USA
基金
美国国家卫生研究院;
关键词
NF-KAPPA-B; HYDROGEN-SULFIDE; CARDIOVASCULAR EVENTS; GOLD NANOPARTICLES; CELL-PROLIFERATION; MOUSE MODEL; IN-VITRO; H2S; GLUTATHIONE; APOPTOSIS;
D O I
10.1371/journal.pone.0079167
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
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页数:12
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