Lactate dehydrogenase A regulates autophagy and tamoxifen resistance in breast cancer

Biochim Biophys Acta Mol Cell Res. 2019 Jun;1866(6):1004-1018. doi: 10.1016/j.bbamcr.2019.03.004. Epub 2019 Mar 13.

Abstract

Estrogen receptor (ER) antagonist, tamoxifen has been universally used for the treatment of the ER-positive breast cancer; however, the inevitable emergence of resistance to tamoxifen obstructs the successful treatment of this cancer. So, there is an immediate requirement for the search of a novel therapeutic target for treatment of this cancer. Acquired tamoxifen-resistant breast cancer cell lines MCF-7 (MCF-7/TAM-R) and T47D (T47D/TAM-R) showed higher apoptotic resistance accompanied by induction of pro-survival autophagy compared to their parental cells. Besides, tamoxifen resistance was associated with reduced production of ATP and with overexpression of glycolytic pathways, leading to induced autophagy to meet the energy demand. Further, our study revealed that LDHA; one of the key molecules of glycolysis in association with Beclin-1 induced pro-survival autophagy in tamoxifen-resistant breast cancer. Mechanistically, pharmacological and genetic inhibition of LDHA reduced the pro-survival autophagy, with the restoration of apoptosis and reverting back the EMT like phenomena noticed in tamoxifen-resistant breast cancer. In total, targeting LDHA opened a novel strategy to interrupt autophagy and tamoxifen resistance in breast cancer.

Keywords: Autophagy; ER-positive breast cancer; Glycolysis; LDHA; Tamoxifen resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagy
  • Beclin-1 / genetics*
  • Breast Neoplasms / genetics*
  • Cell Line, Tumor
  • Cell Survival
  • Drug Resistance, Neoplasm*
  • Epithelial-Mesenchymal Transition
  • Female
  • Glycolysis
  • Humans
  • L-Lactate Dehydrogenase / genetics*
  • MCF-7 Cells
  • Proteasome Endopeptidase Complex / metabolism
  • Tamoxifen / pharmacology*

Substances

  • BECN1 protein, human
  • Beclin-1
  • Tamoxifen
  • L-Lactate Dehydrogenase
  • LDHA protein, human
  • Proteasome Endopeptidase Complex