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Inhibition of autophagy overcomes glucocorticoid resistance in lymphoid malignant cells

Lei Jiang1, Lingzhi Xu, Jiajun Xie

  • 1a Institute of Cancer Stem Cell; Dalian Medical University; Dalian, China; State Key Laboratory of Oncology in South China; Cancer Center; Sun Yat-sen University ; Guangzhou , China.

Cancer Biology & Therapy
|March 18, 2015
PubMed

Insights

Glucocorticoid resistance in lymphoid cancers is a challenge. This study found that inhibiting autophagy, a cellular process, can overcome this resistance and improve treatment outcomes.

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Medicine

Background:

  • Glucocorticoid (GC) resistance is a significant barrier in treating lymphoid malignancies.
  • The exact mechanisms underlying GC resistance are not fully understood.
  • Dexamethasone (Dex) effectively treats sensitive cells but fails in resistant ones.

Purpose of the Study:

  • To elucidate the role of autophagy in dexamethasone (Dex) resistance in lymphoid malignancies.
  • To investigate the potential of targeting autophagy to overcome GC resistance.

Main Methods:

  • Assessing Dex effects on cell proliferation, cell cycle, and apoptosis in sensitive and resistant lymphoid cells.
  • Analyzing autophagy markers (autophagosomes, LC3 conversion, p62 levels, acidic vacuole formation) and mTOR pathway activity (phosphorylation of key proteins).
  • Evaluating the impact of autophagy inhibitors (chloroquine, 3-methyladenine) and Beclin1 knockdown on Dex-resistant cells in vitro and in vivo.

Main Results:

  • Dex induced apoptosis in sensitive cells but failed in resistant cells, where it triggered autophagy.
  • Dex-resistant cells showed increased autophagosome formation, LC3-I to LC3-II conversion, p62 degradation, and acidic autophagic vacuoles.
  • Dex treatment reduced mTOR pathway activity in resistant cells.
  • Inhibiting autophagy with chloroquine or 3-methyladenine restored Dex sensitivity, increasing apoptosis in resistant cells.
  • Stable knockdown of Beclin1 sensitized resistant cells to Dex-induced apoptosis in vivo.

Conclusions:

  • Autophagy is induced by dexamethasone in resistant lymphoid malignant cells.
  • Inhibition of autophagy can overcome GC resistance in lymphoid malignancies.
  • Targeting autophagy presents a potential therapeutic strategy to enhance GC treatment efficacy for lymphoid cancers.
Keywords:
3-MA, 3-methyladenineCQ, chloroquineDex, dexamethasoneDox, doxorubicinLC3, microtubule-associated protein 1 light chain 3MDC, monodansylcadaverineOCT, optimum cutting temperatureRapa, rapamycin; WST-8, 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2, 4-disulfophenyl)-2H- tetrazolium, monosodium saltapoptosisautophagydexamethasoneglucocorticoid resistancelymphoid malignancymTOR, mammalian target of rapamycin

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