Warburg effect in chemosensitivity: Targeting lactate dehydrogenase-A re-sensitizes Taxol-resistant cancer cells to Taxol

Molecular Cancer

Research

Jianrong Lu¹  Sushama Kamarajugadda¹  Susan P Ledoux²  Laurie B Owen³  Yan Ding³  Yuhua Zhao³  Zixing Liu³  Hao Liu³  Ming Zhou⁴  Ming Tan⁵  Oystein Fodstad⁶  Adam I Riker⁷ 

[1] Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida, USA;Department of Cell Biology and Neuroscience, University of South Alabama, Mobile, Alabama, USA;Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA;Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA;Cancer Research Institute, Central South University, Changsha, China;Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA;Department of Cell Biology and Neuroscience, University of South Alabama, Mobile, Alabama, USA;Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA;Institute for Cancer Research, The Norwegian Radium Hospital, University of Oslo, Norway;Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA;Ochsner Cancer Institute, Ochsner Health System, New Orleans, Louisiana, USA;

关键词: Breast Cancer Cell;    Taxol;    Human Breast Cancer Cell;    Mitochondrial Oxidative Phosphorylation;    435TR1 Cell;   

DOI  :  10.1186/1476-4598-9-33

 received in 2009-08-15, accepted in 2010-02-09,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundTaxol is one of the most effective chemotherapeutic agents for the treatment of patients with breast cancer. Despite impressive clinical responses initially, the majority of patients eventually develop resistance to Taxol. Lactate dehydrogenase-A (LDH-A) is one of the predominant isoforms of LDH expressed in breast tissue, which controls the conversion of pyruvate to lactate and plays an important role in glucose metabolism. In this study we investigated the role of LDH-A in mediating Taxol resistance in human breast cancer cells.ResultsTaxol-resistant subclones, derived from the cancer cell line MDA-MB-435, sustained continuous growth in high concentrations of Taxol while the Taxol-sensitive cells could not. The increased expression and activity of LDH-A were detected in Taxol-resistant cells when compared with their parental cells. The downregulation of LDH-A by siRNA significantly increased the sensitivity of Taxol-resistant cells to Taxol. A higher sensitivity to the specific LDH inhibitor, oxamate, was found in the Taxol-resistant cells. Furthermore, treating cells with the combination of Taxol and oxamate showed a synergistical inhibitory effect on Taxol-resistant breast cancer cells by promoting apoptosis in these cells.ConclusionLDH-A plays an important role in Taxol resistance and inhibition of LDH-A re-sensitizes Taxol-resistant cells to Taxol. This supports that Warburg effect is a property of Taxol resistant cancer cells and may play an important role in the development of Taxol resistance. To our knowledge, this is the first report showing that the increased expression of LDH-A plays an important role in Taxol resistance of human breast cancer cells. This study provides valuable information for the future development and use of targeted therapies, such as oxamate, for the treatment of patients with Taxol-resistant breast cancer.

【 授权许可】

Unknown   
© Zhou et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.