Cystathionine: A novel oncometabolite in human breast cancer.
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.
Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095, USA. Electronic address: sen@mednet.ucla.edu.
Suvajit
S
Sen
Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095, USA.
Brain
B
Kawahara
VA San Diego Healthcare System and University of California, San Diego, CA, USA.
Sushil K
SK
Mahata
Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095, USA.
Rebecca
R
Tsai
Semel Institute for Neuroscience and Human Behavior at University of California at Los Angeles, Los Angeles, CA 90095, USA.
Alexander
A
Yoon
Semel Institute for Neuroscience and Human Behavior at University of California at Los Angeles, Los Angeles, CA 90095, USA.
Lin
L
Hwang
Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095, USA.
Kayla
K
Hu-Moore
Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095, USA.
Carissa
C
Villanueva
Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095, USA.
Abdulqadir
A
Vajihuddin
Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095, USA.
Pooja
P
Parameshwar
Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095, USA.
Michelle
M
You
Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095, USA.
Divya Lakshmi
DL
Bhaskar
Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095, USA.
Omar
O
Gomez
Semel Institute for Neuroscience and Human Behavior at University of California at Los Angeles, Los Angeles, CA 90095, USA.
Kym F
KF
Faull
Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095, USA.
Robin
R
Farias-Eisner
Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095, USA.
Gautam
G
Chaudhuri
D000970:Antineoplastic Agents / Q000737:chemistry; D017209:Apoptosis; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D003540:Cystathionine / Q000378:metabolism*; D003541:Cystathionine beta-Synthase / Q000378:metabolism*; D003542:Cystathionine gamma-Lyase / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D061986:MCF-7 Cells; D008854:Microscopy, Electron; D010101:Oxygen Consumption; D010539:Permeability; D017382:Reactive Oxygen Species / Q000378:metabolism
D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D003540:Cystathionine; D003541:Cystathionine beta-Synthase; D003542:Cystathionine gamma-Lyase
Apoptotic threshold; Breast cancer; Cystathionine