TY - JOUR
T1 - Role of cystathionine β-synthase in human breast Cancer
AU - Sen, Suvajit
AU - Kawahara, Brian
AU - Gupta, Divya
AU - Tsai, Rebecca
AU - Khachatryan, Marine
AU - Roy-Chowdhuri, Sinchita
AU - Bose, Shikha
AU - Yoon, Alexander
AU - Faull, Kym
AU - Farias-Eisner, Robin
AU - Chaudhuri, Gautam
N1 - Funding Information:
We acknowledge The Roberta Deutsch Foundation and Kelly Day for their financial support and Svetlana Roberts for technical help. We sincerely thank Prof. Pluth at the University of Oregon, for gifting us HSN2 for intracellular H 2 S measurements. We also acknowledge Ana Maria Cruz, M.S., for her contribution toward editing the language in this manuscript.
Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/7/13
Y1 - 2015/7/13
N2 - Cystathionine β-synthase (CBS) is an enzyme in the transulfuration pathway that can catalyze the condensation of homocysteine (Hcy) and cysteine (Cys) to hydrogen sulfide (H2S) and cystathionine (CTH). CBS-derived H2S is important in angiogenesis and drug resistance in colon and ovarian cancers, respectively. However, the mechanisms by which cancer cell-derived H2S is utilized by cancer cells as a protective agent against host-derived activated macrophages are not yet investigated. This study investigated the mechanistic role of CBS-derived H2S in the protection of human breast cancer (HBC) cells against activated macrophages. HBC patient-derived tissue arrays and immunoblot analysis of HBC cells exhibited significantly increased levels of CBS when compared with their normal counterparts. This was associated with increased levels of H2S and CTH. Silencing of CBS in HBC cells caused a significant decrease in the levels of H2S and CTH but did not affect the growth of these cells per se, in in vitro cultures. However CBS-silenced cells exhibited significantly reduced growth in the presence of activated macrophages and in xenograft models. This was associated with an increase in the steady state levels of reactive aldehyde-derived protein adducts. Exogenous addition of H2S countered the effects of CBS silencing in the presence of macrophages. Conversely overexpression of CBS in human breast epithelial (HBE) cells (which do not naturally express CBS) protected them from activated macrophages, which were otherwise susceptible to the latter.
AB - Cystathionine β-synthase (CBS) is an enzyme in the transulfuration pathway that can catalyze the condensation of homocysteine (Hcy) and cysteine (Cys) to hydrogen sulfide (H2S) and cystathionine (CTH). CBS-derived H2S is important in angiogenesis and drug resistance in colon and ovarian cancers, respectively. However, the mechanisms by which cancer cell-derived H2S is utilized by cancer cells as a protective agent against host-derived activated macrophages are not yet investigated. This study investigated the mechanistic role of CBS-derived H2S in the protection of human breast cancer (HBC) cells against activated macrophages. HBC patient-derived tissue arrays and immunoblot analysis of HBC cells exhibited significantly increased levels of CBS when compared with their normal counterparts. This was associated with increased levels of H2S and CTH. Silencing of CBS in HBC cells caused a significant decrease in the levels of H2S and CTH but did not affect the growth of these cells per se, in in vitro cultures. However CBS-silenced cells exhibited significantly reduced growth in the presence of activated macrophages and in xenograft models. This was associated with an increase in the steady state levels of reactive aldehyde-derived protein adducts. Exogenous addition of H2S countered the effects of CBS silencing in the presence of macrophages. Conversely overexpression of CBS in human breast epithelial (HBE) cells (which do not naturally express CBS) protected them from activated macrophages, which were otherwise susceptible to the latter.
KW - 4-Hydroxynonenal
KW - Breast cancer
KW - Cystathionine β-synthase
KW - Hydrogen sulfide
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U2 - 10.1016/j.freeradbiomed.2015.05.024
DO - 10.1016/j.freeradbiomed.2015.05.024
M3 - Article
C2 - 26051168
AN - SCOPUS:84936932890
SN - 0891-5849
VL - 86
SP - 228
EP - 238
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
ER -