Cystathionine: A novel oncometabolite in human breast cancer

• Published in: Archives of biochemistry and biophysics Vol. 604; pp. 95 - 102
• Main Authors: Sen, Suvajit, Kawahara, Brain, Mahata, Sushil K., Tsai, Rebecca, Yoon, Alexander, Hwang, Lin, Hu-Moore, Kayla, Villanueva, Carissa, Vajihuddin, Abdulqadir, Parameshwar, Pooja, You, Michelle, Bhaskar, Divya Lakshmi, Gomez, Omar, Faull, Kym F., Farias-Eisner, Robin, Chaudhuri, Gautam
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.08.2016
• Subjects: Antineoplastic Agents - chemistry; Apoptosis; Apoptotic threshold; Breast cancer; Breast Neoplasms - metabolism; Cell Line, Tumor; Cell Survival; Cystathionine; Cystathionine - metabolism; Cystathionine beta-Synthase - metabolism; Cystathionine gamma-Lyase - metabolism; Cytosol - metabolism; Drug Resistance, Neoplasm; Endoplasmic Reticulum - metabolism; Female; Humans; Immunohistochemistry; MCF-7 Cells; Microscopy, Electron; Oxygen Consumption; Permeability; Reactive Oxygen Species - metabolism; Cystathionine; Breast cancer; Apoptotic threshold
• ISSN: 0003-9861; 1096-0384
• DOI: 10.1016/j.abb.2016.06.010

In this study, we have identified cystathionine (CTH), a sulfur containing metabolite, to be selectively enriched in human breast cancer (HBC) tissues (∼50–100 pmoles/mg protein) compared with undetectable levels in normal breast tissues. The accumulation of CTH, specifically in HBC, was attributed to the overexpression of cystathionine beta synthase (CBS), its synthesizing enzyme, and the undetectable levels of its downstream metabolizing enzyme, cystathionine gamma lyase (CGL). Interestingly both CBS and CGL could not be detected in normal breast tissues. We further observed that CTH protected HBC cells against excess reactive oxygen species (ROS) and chemotherapeutic drug-induced apoptosis. Moreover, CTH promoted both mitochondrial and endoplasmic reticulum homeostasis in HBC cells. As both the mitochondria and the endoplasmic reticulum are key organelles regulating the onset of apoptosis, we reasoned that endogenous CTH could be contributing towards increasing the apoptotic threshold in HBC cells. An increased apoptotic threshold is a hallmark of all cancer types, including HBC, and is primarily responsible for drug resistance. Hence this study unravels one of the possible pathways that may contribute towards drug resistance in HBC. [Display omitted] •Human Breast Cancer tissues accumulate cystathionine.•Cystathionine promotes endoplasmic reticulum and mitochondrial homeostasis.•Cystathionine plays an anti-apoptotic role in Human Breast Cancer Cells.