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

Abstract

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

The Therapeutic Potential of Cystathionine β-Synthetase/Hydrogen Sulfide Inhibition in Cancer

“…Our findings of colorectal cancers have recently been confirmed in ovarian cancer (10). These investigators assessed the expression level of CBS in primary ovarian cancer specimens, and found high expression of CBS in the cytosol of primary ovarian tumors, especially in serous carcinoma, as well as in various ovarian cancer cell lines (Fig.…”

“…CBS silencing resulted in a significant decrease in proliferation in all ovarian cancer cell lines studied ( Fig. 8) (10). Similar to HCT116 cells, CBS silencing in A2870 ovarian cancer cells markedly suppressed cellular metabolism (mitochondrial electron transport); both basal oxygen consumption responses and the enhanced respiratory responses induced by a mitochondrial uncoupler were inhibited (10).…”

“…7). CBS was already present in early stages, but its levels further increased in more advanced forms of ovarian cancer (10).…”

“…Similar to HCT116 cells, CBS silencing in A2870 ovarian cancer cells markedly suppressed cellular metabolism (mitochondrial electron transport); both basal oxygen consumption responses and the enhanced respiratory responses induced by a mitochondrial uncoupler were inhibited (10). The effects of CBS silencing were also associated with a decrease in cellular NAD/NADH ratio, a partial suppression of cellular ATP levels, and a significant decrease in cell viability (10). Similar to our earlier findings in colon cancer cells, a large proportion of CBS in ovarian cancer cells was localized to the mitochondrial compartment ( Fig.…”

Modes of Physiologic H2S Signaling in the Brain and Peripheral Tissues

“…Reducing CBS activity results in lower cell proliferation and reduced endothelial cell migration in tumor/endothelial cell cocultures. The proliferative effects of CBS and its role in bioenergetics were also observed in ovarian carcinoma (6). Primary epithelial ovarian cancer tissues and ovarian cancer cell lines exhibited increased expression of CBS.…”