Autophagy upregulation by inhibitors of caspase-3 and mTOR enhances radiotherapy in a mouse model of lung cancer

Woon Kim Kwang, Misun Hwang, Luigi Moretti, Jerry Jaboin, Yong I. Cha, Bo Lu

Research output: Contribution to journalArticle

121 Citations (Scopus)

Abstract

Autophagy has been reported to be increased in irradiated cancer cells resistant to various apoptotic stimuli. We therefore hypothesized that induction of autophagy via mTOR inhibition could enhance radiosensitization in apoptosis-inhibited H460 lung cancer cells in vitro and in a lung cancer xenograft model. To test this hypothesis, combinations of Z-DEVD (caspase-3 inhibitor), RAD001 (mTOR inhibitor) and irradiation were tested in cell and mouse models. The combination of Z-DEVD and RAD001 more potently radio sensitized H460 cells than individual treatment alone. The enhancement in radiation response was not only evident in clonogenic survival assays, but also was demonstrated through markedly reduced tumor growth, cellular proliferation (Ki67 staining), apoptosis (TUNEL staining) and angiogenesis (vWF staining) in vivo. Additionally, upregulation of autophagy as measured by increased GFP-LC3-tagged autophagosome formation accompanied the noted radiosensitization in vitro and in vivo. The greatest induction of autophagy and associated radiation toxicity was exhibited in the tri-modality treatment group. Autophagy marker, LC3-II, was reduced by 3-methyladenine (3-MA), a known inhibitor of autophagy, but further increased by the addition of lysosomal protease inhibitors (pepstatin A and E64d), demonstrating that there is autophagic induction through type III PI3 kinase during the combined therapy Knocking down of ATG5 and beclin-1, two essential autophagic molecules, resulted in radiation resistance of lung cancer cells. Our report suggests that combined inhibition of apoptosis and mTOR during radiotherapy is a potential therapeutic strategy to enhance radiation therapy in patients with non-small cell lung cancer.

Original languageEnglish (US)
Pages (from-to)659-668
Number of pages10
JournalAutophagy
Volume4
Issue number5
StatePublished - Jul 1 2008
Externally publishedYes

Fingerprint

Autophagy
Caspase 3
Lung Neoplasms
Up-Regulation
Radiotherapy
Radiation
Apoptosis
Staining and Labeling
Caspase Inhibitors
In Situ Nick-End Labeling
Therapeutics
Radio
Phosphatidylinositol 3-Kinases
Heterografts
Non-Small Cell Lung Carcinoma
Neoplasms
Cell Proliferation
Survival
Growth

Keywords

  • Autophagy
  • Caspase
  • Lung cancer
  • mTOR
  • Radiotherapy

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Autophagy upregulation by inhibitors of caspase-3 and mTOR enhances radiotherapy in a mouse model of lung cancer. / Kwang, Woon Kim; Hwang, Misun; Moretti, Luigi; Jaboin, Jerry; Cha, Yong I.; Lu, Bo.

In: Autophagy, Vol. 4, No. 5, 01.07.2008, p. 659-668.

Research output: Contribution to journalArticle

Kwang, WK, Hwang, M, Moretti, L, Jaboin, J, Cha, YI & Lu, B 2008, 'Autophagy upregulation by inhibitors of caspase-3 and mTOR enhances radiotherapy in a mouse model of lung cancer', Autophagy, vol. 4, no. 5, pp. 659-668.
Kwang, Woon Kim ; Hwang, Misun ; Moretti, Luigi ; Jaboin, Jerry ; Cha, Yong I. ; Lu, Bo. / Autophagy upregulation by inhibitors of caspase-3 and mTOR enhances radiotherapy in a mouse model of lung cancer. In: Autophagy. 2008 ; Vol. 4, No. 5. pp. 659-668.
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