Autophagy for cancer therapy through inhibition of pro-apoptotic proteins and mammalian target of rapamycin signaling

Woon Kim Kwang, Robert Mutter, Carolyn Cao, Jeffrey M. Albert, Michael Freeman, Dennis E. Hallahan, Bo Lu

Research output: Contribution to journalArticle

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Abstract

Autophagy is an alternative cell death pathway that is induced by mammalian target of rapamycin (mTOR) inhibitors and upregulated when apoptosis is defective. We investigated radiation-induced autophagy in the presence or absence of Bax/Bak with or without an mTOR inhibitor, Rad001. Two isogenic cell lines, wild type (WT) and Bak/Bak-/- mouse embryonic fibroblasts and tumor cell lines were used for this study. Irradiated Bak/Bak-/- cells had a decrease of Akt/mTOR signaling and a significant increase of pro-autophagic proteins ATG5-ATG12 COMPLEX and Beclin-1. These molecular events resulted in an up-regulation of autophagy. Bax/Bak-/- cells were defective in undergoing apoptosis but were more radiosensitive than the WT cells in autophagy. Both autophagy and sensitization of Bak/Bax-/- cells were further enhanced in the presence of Rad001. In contrast, inhibitors of autophagy rendered the Bak/Bax-/- cells radioresistant, whereas overexpression of ATG5 and Beclin-1 made the WT cells radiosensitive. When this novel concept of radiosensitization was tested in cancer models, small interfering RNAs against Bak/Bax also led to increased autophagy and sensitization of human breast and lung cancer cells to gamma radiation, which was further enhanced by Rad001. This is the first report to demonstrate that inhibition of pro-apoptotic proteins and induction of autophagy sensitizes cancer cells to therapy. Therapeutically targeting this novel pathway may yield significant benefits for cancer patients.

Original languageEnglish (US)
Pages (from-to)36883-36890
Number of pages8
JournalJournal of Biological Chemistry
Volume281
Issue number48
DOIs
StatePublished - Dec 1 2006
Externally publishedYes

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Apoptosis Regulatory Proteins
Autophagy
Sirolimus
Cells
Neoplasms
Apoptosis
Cell death
Fibroblasts
Therapeutics
Gamma rays
Small Interfering RNA
Tumors
Radiation
Gamma Rays
Cell- and Tissue-Based Therapy
Tumor Cell Line
Everolimus
Lung Neoplasms
Proteins
Cell Death

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Autophagy for cancer therapy through inhibition of pro-apoptotic proteins and mammalian target of rapamycin signaling. / Kwang, Woon Kim; Mutter, Robert; Cao, Carolyn; Albert, Jeffrey M.; Freeman, Michael; Hallahan, Dennis E.; Lu, Bo.

In: Journal of Biological Chemistry, Vol. 281, No. 48, 01.12.2006, p. 36883-36890.

Research output: Contribution to journalArticle

Kwang, Woon Kim ; Mutter, Robert ; Cao, Carolyn ; Albert, Jeffrey M. ; Freeman, Michael ; Hallahan, Dennis E. ; Lu, Bo. / Autophagy for cancer therapy through inhibition of pro-apoptotic proteins and mammalian target of rapamycin signaling. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 48. pp. 36883-36890.
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