July 17, 2018
Statistical data of Taiwan’s Ministry of Health and Welfare indicate that breast cancer is the leading cause of cancer death in women. Although common subtypes of breast cancer have a 5 years survival rate of over 85%, certain subtypes such as basal like triple negative breast cancer (TNBC) displays very poor prognosis and survival rates. To date, there is no targeted therapy for TNBC. A number of studies have shown that metabolic reprogramming plays a crucial role in cancer progression. Tumor cells generally have high requirements of glucose metabolism for rapid proliferation. Identification of metabolic enzymes and oncometabolites regulating breast cancer metastasis could reveal useful therapeutic targets.
Dr. Lu-Hai Wang’s team collaborated with Dr. King-Jen Chang and Dr. Wen-Hong Kuo in the Breast Center of National Taiwan University Hospital had uncovered metabolic pathways controlling growth and metastasis of breast cancer cells. They revealed that glucose metabolic enzyme transketolase (TKT) played an important role in regulating dynamic switch of glucose metabolism, leading to the control of growth and metastasis of TNBC. The finding further demonstrates the important role of metabolic reprogramming in tumorigenesis and progression. This study has been published in Cancer Research in June, 2018.
In normal cells, glucose metabolism proceeds mainly via aerobic respiration inside the mitochondria (85%) and only a small percentage (5-10%) via anaerobic glycolysis to generate needed high energy molecule ATPs. On the contrary, tumor cells drive reprogramming of glucose metabolism to increase glucose update and undergo mainly glycolysis (85%) while only a small percentage (5-10%) proceeds via oxidative phosphorylation in mitochondria. This is due to the need to provide energy and building stones needed for rapid growth of tumor cells. This phenomenon is known as Warburg effect and is the common property of tumor cells.
Dr. Lu-Hai Wang’s team observed that the expression levels of transketolase (TKT) increased with tumor size in the 4T1/BALB/c syngeneic mouse model. Moreover, TKT expression was higher in lymph node metastases compared with primary tumor or normal tissues of patients, and high TKT levels were associated with poor survival. Depletion of TKT enhanced alpha-ketoglutarate (α-KG) levels in breast cancer cells. Reduced TKT or addition of α-KG to cancer cells mediated a dynamic switch of glucose metabolism from glycolysis to oxidative phosphorylation, resulting in suppressing breast cancer cell growth and metastasis. It was further shown that depletion of TKT or administration of α-KG in mouse model suppressed tumor growth as well as lymph node and lung metastasis. Combinations of the TKT inhibitor oxythiamine with docetaxel and/or doxorubicin enhanced TNBC cancer cell death in vitro and tumor growth in the mouse model.
Together, the study has revealed that depletion of TKT or addition of α-KG to cancer cells shifts their glucose metabolism from glycolysis toward oxidative phosphorylation and thus inhibit the growth and metastasis. This study identifies a novel TKT-mediated α-KG signaling pathway that regulates breast cancer oncogenesis. TKT inhibitor and α-KG can be exploited as the modality for cancer therapy.
For the full text of our publication in Cancer Research, please visit: http://cancerres.aacrjournals.org/content/78/11/2799.long
Dr. Lu-Hai Wang, NHRI Investigator Emeritus, Institutes of Molecular and Genomic Medicine, National Health Research Institutes, TEL: +886-4-2205-7153, E-mail: firstname.lastname@example.org
Nathalie Huang, Secretariat, National Health Research Institutes, TEL: +886-37-246-166 ext.32113, E-mail: email@example.com