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

Sanjib Bhattacharyya, Sounik Saha, Karuna Giri, Ian R Lanza, K Sreekumaran Nair, Nicholas B. Jennings, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Eati Basal, Amy L. Weaver, Daniel W Visscher, William Arthur Cliby, Anil K. Sood, Resham Bhattacharya, Priyabrata Mukherjee

Research output: Contribution to journalArticle

98 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere79167
JournalPLoS One
Volume8
Issue number11
DOIs
StatePublished - Nov 13 2013

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cystathionine beta-synthase
Cystathionine beta-Synthase
ovarian neoplasms
drug resistance
Drug Resistance
Ovarian Neoplasms
Pharmaceutical Preparations
platinum
Platinum
Tumors
cisplatin
Cells
relapse
Sulfur
Metabolism
energy metabolism
Energy Metabolism
Cisplatin
neoplasms
carcinoma

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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Cystathionine Beta-Synthase (CBS) Contributes to Advanced Ovarian Cancer Progression and Drug Resistance. / Bhattacharyya, Sanjib; Saha, Sounik; Giri, Karuna; Lanza, Ian R; Nair, K Sreekumaran; Jennings, Nicholas B.; Rodriguez-Aguayo, Cristian; Lopez-Berestein, Gabriel; Basal, Eati; Weaver, Amy L.; Visscher, Daniel W; Cliby, William Arthur; Sood, Anil K.; Bhattacharya, Resham; Mukherjee, Priyabrata.

In: PLoS One, Vol. 8, No. 11, e79167, 13.11.2013.

Research output: Contribution to journalArticle

Bhattacharyya, S, Saha, S, Giri, K, Lanza, IR, Nair, KS, Jennings, NB, Rodriguez-Aguayo, C, Lopez-Berestein, G, Basal, E, Weaver, AL, Visscher, DW, Cliby, WA, Sood, AK, Bhattacharya, R & Mukherjee, P 2013, 'Cystathionine Beta-Synthase (CBS) Contributes to Advanced Ovarian Cancer Progression and Drug Resistance', PLoS One, vol. 8, no. 11, e79167. https://doi.org/10.1371/journal.pone.0079167
Bhattacharyya, Sanjib ; Saha, Sounik ; Giri, Karuna ; Lanza, Ian R ; Nair, K Sreekumaran ; Jennings, Nicholas B. ; Rodriguez-Aguayo, Cristian ; Lopez-Berestein, Gabriel ; Basal, Eati ; Weaver, Amy L. ; Visscher, Daniel W ; Cliby, William Arthur ; Sood, Anil K. ; Bhattacharya, Resham ; Mukherjee, Priyabrata. / Cystathionine Beta-Synthase (CBS) Contributes to Advanced Ovarian Cancer Progression and Drug Resistance. In: PLoS One. 2013 ; Vol. 8, No. 11.
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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.",
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AU - Nair, K Sreekumaran

AU - Jennings, Nicholas B.

AU - Rodriguez-Aguayo, Cristian

AU - Lopez-Berestein, Gabriel

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AU - Weaver, Amy L.

AU - Visscher, Daniel W

AU - Cliby, William Arthur

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