Cystathionine beta-synthase (CBS) contributes to advanced ovarian cancer progression and drug resistance

• Published in: PloS one 2013-11, Vol.8 (11), p.e79167
• Main Authors: Bhattacharyya, Sanjib, Saha, Sounik, Giri, Karuna, Lanza, Ian R, Nair, K Sreekumar, Jennings, Nicholas B, Rodriguez-Aguayo, Cristian, Lopez-Berestein, Gabriel, Basal, Eati, Weaver, Amy L, Visscher, Daniel W, Cliby, William, Sood, Anil K, Bhattacharya, Resham, Mukherjee, Priyabrata
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - biosynthesis; Adult; Aged; Aged, 80 and over; Analysis; Animals; Antioxidants - metabolism; Apoptosis; Biochemistry; Bioenergetics; Brain cancer; Cancer; Cancer metastasis; Cardiovascular disease; Cell growth; Cell Line, Tumor; Cell Proliferation; Chemotherapy; Cisplatin; Cisplatin - pharmacology; Cystathionine b-synthase; Cystathionine beta-Synthase - genetics; Cystathionine beta-Synthase - metabolism; Cytotoxicity; Disease Models, Animal; Disease Progression; Drug resistance; Drug Resistance, Neoplasm - genetics; Drug therapy; Endocrinology; Enzymes; Female; Gene Expression; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Gene Silencing; Gynecology; Health aspects; Humans; Hydrogen; Hydrogen sulfide; Immunohistochemistry; Impact resistance; In vivo methods and tests; Kinases; Laboratory animals; Mammals; Medical research; Medicine; Metabolism; Metastases; Mice; Middle Aged; Mitochondria; Mitochondria - metabolism; Molecular biology; Neoplasm Grading; Neoplasm Staging; Nodules; Obstetrics; Ovarian cancer; Ovarian carcinoma; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Oxidative stress; Oxygen; Oxygen consumption; Pathology; Phenotype; Phenotypes; Physiological aspects; Platinum; Ribonucleic acid; RNA; Rodents; siRNA; Sodium sulfide; Sulfur; Sulfur compounds; Supplementation; Supplements; Surgery; Therapeutic applications; Tumor Burden - drug effects; Tumor Burden - genetics; Young Adult
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0079167

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. 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. The present investigation highlights CBS as a potential therapeutic target in relapsed and platinum resistant ovarian cancer.