Bhattacharyya 2013 PLoS One

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 W, Sood AK, Bhattacharya R, Mukherjee P (2013) Cystathionine Beta-Synthase (CBS) Contributes to Advanced Ovarian Cancer Progression and Drug Resistance. PLoS One [Epub ahead of print].

» PMID: 24236104

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 W, Sood AK, Bhattacharya R, Mukherjee P (2013) PLoS One

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.

• O2k-Network Lab: US MN Rochester Nair KS

Labels: MiParea: Respiration, Genetic knockout;overexpression, mt-Medicine  Pathology: Cancer 

Organism: Human  Tissue;cell: Genital  Preparation: Intact cells  Enzyme: TCA Cycle and Matrix Dehydrogenases"TCA Cycle and Matrix Dehydrogenases" is not in the list (Adenine nucleotide translocase, Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase, Complex V;ATP synthase, Inner mt-membrane transporter, Marker enzyme, Supercomplex, TCA cycle and matrix dehydrogenases, ...) of allowed values for the "Enzyme" property. 

Coupling state: ROUTINE, ETS"ETS" is not in the list (LEAK, ROUTINE, OXPHOS, ET) of allowed values for the "Coupling states" property. 

HRR: Oxygraph-2k