Breast Cancer Research and Treatment

, Volume 131, Issue 3, pp 791–800 | Cite as

LDH-A silencing suppresses breast cancer tumorigenicity through induction of oxidative stress mediated mitochondrial pathway apoptosis

  • Zhi-Yu Wang
  • Tjing Yung Loo
  • Jian-Gang Shen
  • Neng Wang
  • Dong-Mei Wang
  • De-Po Yang
  • Sui-Lin Mo
  • Xin-Yuan Guan
  • Jian-Ping Chen
Preclinical Study

Abstract

LDH-A, as the critical enzyme accounting for the transformation from pyruvate into lactate, has been demonstrated to be highly expressed in various cancer cells and its silencing has also been approved relating to increased apoptosis in lymphoma cells. In this study, we intend to investigate the correlation between LDH-A and other clinicopathological factors of breast cancer and whether LDH-A silencing could suppress breast cancer growth, and if so the potential mechanisms. 46 breast cancer specimens were collected to study the relation between LDH-A expression and clinicopathological characteristics including menopause, tumor size, node involvement, differentiation, and pathological subtypes classified by ER, PR, and Her-2. shRNAs were designed and applied to silence LDH-A expression in breast cancer cell lines MCF-7 and MDA-MB-231. The effects of LDH-A reduction on cancer cells were studied by a series of in vitro and in vivo experiments, including cell growth assay, apoptosis evaluation, oxidative stress detection, transmission electron microscopy observation, and tumor formation assay on nude mice. LDH-A expression was found to correlate significantly with tumor size and to be independent for other clinicopathological factors. LDH-A reduction resulted in an inhibited cancer cell proliferation, elevated intracellular oxidative stress, and induction of mitochondrial pathway apoptosis. Meanwhile, the tumorigenic ability of LDH-A deficient cancer cells was significantly limited in both breast cancer xenografts. The Ki67 positive cancer cells were significantly reduced in LDH-A deficiency tumor samples, while the apoptosis ratio was enhanced. Our results suggested that LDH-A inhibition might offer a promising therapeutic strategy for breast cancer.

Keywords

LDH-A Breast cancer Apoptosis Oxidative stress Mitochondrion 

Abbreviations

LDH-A

Lactate dehydrogenase A

ATP

Adenasine triphosphate

Her-2

Human epidermal growth factor receptor 2

G6PD

Glucose-6-phosphate dehydrogenase

GAPDH

Glyceraldehyde 3-phosphate dehydrogenase

TKTL1

Transketolase-like protein 1

NADH

Nicotinamide adenine dinucleotide reduced disodium salt

TCA

Tricarboxylic acid

ER

Estrogen receptor

PR

Progesterone receptor

shRNA

Short hairpin RNA

ROS

Reactive oxygen species

NAC

N-acetylcysteine

OXPHOS

Oxidative phosphorylation

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Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Zhi-Yu Wang
    • 1
  • Tjing Yung Loo
    • 2
  • Jian-Gang Shen
    • 1
  • Neng Wang
    • 1
  • Dong-Mei Wang
    • 3
  • De-Po Yang
    • 3
  • Sui-Lin Mo
    • 5
  • Xin-Yuan Guan
    • 4
  • Jian-Ping Chen
    • 1
  1. 1.School of Chinese MedicineThe University of Hong KongHong KongChina
  2. 2.Unimed Medical InstituteHong KongChina
  3. 3.School of Pharmaceutical ScienceSun Yat-sen UniversityGuangzhouChina
  4. 4.Department of Clinical OncologyThe University of Hong KongHong KongChina
  5. 5.The First Affiliated HospitalSun Yat-sen UniversityGuangzhouChina

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