Akt is the downstream target of GRP78 in mediating cisplatin resistance in ER stress-tolerant human lung cancer cells

Lung Cancer. 2011 Mar;71(3):291-7. doi: 10.1016/j.lungcan.2010.06.004.

Abstract

Cisplatin [cis-diaminodichloroplatinum (II) (CDDP)] is the cornerstone of lung cancer chemotherapy. However, its efficacy is limited due to the development of drug resistance in cancer cells. This study was designed to uncover the mechanisms under CDDP resistance in lung cancer cells involving endoplasmic reticulum (ER) stress tolerance-induced and GRP78-dependant Akt activation. In this study we established ER stress-tolerant (ERST) human lung cancer lines H460et and A549et. We found that the ERST Lung cancer cells are resistant to CDDP treatment. We further showed that, compared to the parental cell lines, H460et and A549et show significantly increased GRP78 and phospho(p)-Akt levels. And phosphorylation of Akt, which can be regulated by GRP78, is essential to the ERST-associated CDDP resistance. Our findings identify a new mechanism of regulating Akt activity and a new mechanism through which CDDP resistance is formed in lung cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cisplatin / pharmacology*
  • Drug Resistance, Neoplasm / genetics*
  • Endoplasmic Reticulum / drug effects*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Knockdown Techniques
  • Heat-Shock Proteins / metabolism*
  • Humans
  • Lung Neoplasms / drug therapy*
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism*
  • RNA Interference
  • Signal Transduction / drug effects

Substances

  • Antineoplastic Agents
  • Heat-Shock Proteins
  • Proto-Oncogene Proteins c-akt
  • Cisplatin
  • molecular chaperone GRP78