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


RESULTS
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.


CONCLUSIONS
The present investigation highlights CBS as a potential therapeutic target in relapsed and platinum resistant ovarian cancer.
Department of Biochemistry and Molecular Biology, College of Medicine, Mayo Clinic Rochester, Minnesota, United States of America.
Sanjib
S
Bhattacharyya
Sounik
S
Saha
Karuna
K
Giri
Ian R
IR
Lanza
K Sreekumar
KS
Nair
Nicholas B
NB
Jennings
Cristian
C
Rodriguez-Aguayo
Gabriel
G
Lopez-Berestein
Eati
E
Basal
Amy L
AL
Weaver
Daniel W
DW
Visscher
William
W
Cliby
Anil K
AK
Sood
Resham
R
Bhattacharya
Priyabrata
P
Mukherjee
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology; D003541:Cystathionine beta-Synthase / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D055815:Young Adult
D000975:Antioxidants; D000255:Adenosine Triphosphate; D003541:Cystathionine beta-Synthase; D002945:Cisplatin