Role of cystathionine β-synthase in human breast Cancer

Suvajit Sen; Brian Kawahara; Divya Gupta; Rebecca Tsai; Marine Khachatryan; Sinchita Roy-Chowdhuri; Shikha Bose; Alexander Yoon; Kym Faull; Robin Farias-Eisner; Gautam Chaudhuri

doi:10.1016/j.freeradbiomed.2015.05.024

Role of cystathionine β-synthase in human breast Cancer

Free Radic Biol Med. 2015 Sep:86:228-38. doi: 10.1016/j.freeradbiomed.2015.05.024. Epub 2015 Jun 4.

Authors

Affiliations

¹ Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095, USA; The Jonsson Cancer Center, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095, USA. Electronic address: ssen@mednet.ucla.edu.
² Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Pathology at MD Anderson School of Medicine, Houston, TX 77054, USA.
⁴ Pathology and Laboratory Medicine at Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁵ Semel Institute for Neuroscience and Human Behavior at University of California at Los Angeles, Los Angeles, CA 90095, USA.
⁶ The Jonsson Cancer Center, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095, USA; Semel Institute for Neuroscience and Human Behavior at University of California at Los Angeles, Los Angeles, CA 90095, USA.
⁷ Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095, USA; The Jonsson Cancer Center, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095, USA; Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095, USA.

PMID: 26051168
DOI: 10.1016/j.freeradbiomed.2015.05.024

Abstract

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.

Keywords: 4-Hydroxynonenal; Breast cancer; Cystathionine β-synthase; Hydrogen sulfide.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Breast Neoplasms / enzymology*
Breast Neoplasms / immunology
Breast Neoplasms / pathology
Cell Membrane / enzymology
Coculture Techniques
Cystathionine beta-Synthase / physiology*
Female
Glutathione / metabolism
Humans
Hydrogen Sulfide / pharmacology
Lymphatic Metastasis
MCF-7 Cells
Macrophages / immunology
Mice, Inbred BALB C
Mice, Nude
Neoplasm Transplantation

Substances

Cystathionine beta-Synthase
Glutathione
Hydrogen Sulfide