The Effect of TIGAR Knockdown on Apoptotic and Epithelial-Mesenchymal Markers Expression in Doxorubicin-Resistant Non-Small Cell Lung Cancer A549 Cell Lines

Chem Biodivers. 2020 Sep;17(9):e2000441. doi: 10.1002/cbdv.202000441. Epub 2020 Sep 3.

Abstract

Resistance to chemotherapeutic drugs is a critical problem in cancer therapy, but the underlying mechanism has not been fully elucidated. TP53-induced glycolysis regulatory phosphatase (TIGAR), an important glycolysis and apoptosis regulator, plays a crucial role in cancer cell survival by protecting cells against oxidative stress-induced apoptosis. In the present study, we investigated whether TIGAR is involved in epithelial-mesenchymal transition (EMT) in doxorubicin (DOX)-resistant human non-small cell lung cancer (NSCLC), A549/DOX cells. We found that the expression of TIGAR was significantly higher in A549/DOX cells than in the parent A549 cell lines. siRNA-mediated TIGAR knockdown reduced migration, viability and colony survival of doxorubicin-resistant lung cancer cells. Also, TIGAR knockdown decreased pro-survival protein Bcl-2 and increased pro-apoptotic Bax and cleaved poly (ADP-ribose) polymerase (PARP). Moreover, TIGAR depletion significantly up-regulated both caspase-3 and caspase-9 expression. Furthermore, TIGAR depletion up-regulated the expression of E-cadherin and down-regulated the expression of vimentin. These results indicate that TIGAR knockdown may inhibit EMT in doxorubicin (DOX)-resistant human NSCLC and may represent a therapeutic target for a non-small lung cancer cells chemoresistance.

Keywords: TIGAR; antitumor agents; apoptosis; epithelial-mesenchymal transition (EMT); lung cancer.

MeSH terms

  • A549 Cells
  • Antibiotics, Antineoplastic / pharmacology
  • Apoptosis Regulatory Proteins / deficiency
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Apoptosis* / drug effects
  • Biomarkers, Tumor / genetics*
  • Biomarkers, Tumor / metabolism
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Movement / drug effects
  • Cell Survival / drug effects
  • Doxorubicin / pharmacology
  • Drug Resistance, Neoplasm / drug effects
  • Epithelial-Mesenchymal Transition / drug effects
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Phosphoric Monoester Hydrolases / deficiency
  • Phosphoric Monoester Hydrolases / genetics
  • Phosphoric Monoester Hydrolases / metabolism*
  • RNA, Small Interfering / metabolism*
  • Tumor Cells, Cultured

Substances

  • Antibiotics, Antineoplastic
  • Apoptosis Regulatory Proteins
  • Biomarkers, Tumor
  • RNA, Small Interfering
  • Doxorubicin
  • Phosphoric Monoester Hydrolases
  • TIGAR protein, human