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.
Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095, USA.
Free Radic Biol Med. 2015 Sep;86:228-38. doi: 10.1016/j.freeradbiomed.2015.05.024. Epub 2015 Jun 4.
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.
胱硫醚β-合酶（CBS）是转硫途径中的一种酶，能够催化同型半胱氨酸（Hcy）和半胱氨酸（Cys）缩合生成硫化氢（H2S）和胱硫醚（CTH）。CBS 衍生的 H2S 分别在结肠癌和卵巢癌的血管生成和耐药性中起重要作用。然而，癌细胞衍生的 H2S 如何被癌细胞用作对抗宿主来源的活化巨噬细胞的保护剂的机制尚未研究。本研究探讨了 CBS 衍生的 H2S 在保护人乳腺癌（HBC）细胞免受活化巨噬细胞侵害中的作用机制。与正常细胞相比，HBC 患者来源的组织阵列和 HBC 细胞的免疫印迹分析显示 CBS 水平显著升高。这与 H2S 和 CTH 水平的升高有关。在 HBC 细胞中沉默 CBS 会导致 H2S 和 CTH 水平显著降低，但本身不会影响这些细胞的生长。然而，在活化的巨噬细胞存在下和异种移植模型中，沉默 CBS 的细胞的生长显著减少。这与反应性醛衍生的蛋白加合物的稳定状态水平增加有关。外源性添加 H2S 可抵消巨噬细胞存在时 CBS 沉默的作用。相反，CBS 在人乳腺上皮（HBE）细胞中的过表达（HBE 细胞本身不自然表达 CBS）保护了它们免受活化的巨噬细胞的侵害，而巨噬细胞本身容易受到后者的侵害。
