Role of autophagy in histone deacetylase inhibitor-induced apoptotic and nonapoptotic cell death Journal Article

Authors: Gammoh, N.; Lam, D.; Puente, C.; Ganley, I.; Marks, P. A.; Jiang, X.
Article Title: Role of autophagy in histone deacetylase inhibitor-induced apoptotic and nonapoptotic cell death
Abstract: Autophagy is a cellular catabolic pathway by which long-lived proteins and damaged organelles are targeted for degradation. Activation of autophagy enhances cellular tolerance to various stresses. Recent studies indicate that a class of anticancer agents, histone deacetylase (HDAC) inhibitors, can induce autophagy. One of the HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA), is currently being used for treating cutaneous T-cell lymphoma and under clinical trials for multiple other cancer types, including glioblastoma. Here, we show that SAHA increases the expression of the autophagic factor LC3, and inhibits the nutrient-sensing kinase mammalian target of rapamycin (mTOR). The inactivation of mTOR results in the dephosphorylation, and thus activation, of the autophagic protein kinase ULK1, which is essential for autophagy activation during SAHA treatment. Furthermore, we show that the inhibition of autophagy by RNAi in glioblastoma cells results in an increase in SAHA-induced apoptosis. Importantly, when apoptosis is pharmacologically blocked, SAHA-induced non-apoptotic cell death can also be potentiated by autophagy inhibition. Overall, our findings indicate that SAHA activates autophagy via inhibiting mTOR and up-regulating LC3 expression; autophagy functions as a prosurvival mechanism to mitigate SAHA-induced apoptotic and nonapoptotic cell death, suggesting that targeting autophagy might improve the therapeutic effects of SAHA.
Keywords: controlled study; nonhuman; animal cell; mouse; cell death; apoptosis; enzyme inhibition; necrosis; mammalian target of rapamycin; enzyme inactivation; transcription; vorinostat; upregulation; autophagy; dephosphorylation; atg7
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 109
Issue: 17
ISSN: 0027-8424
Publisher: National Academy of Sciences  
Date Published: 2012-04-24
Start Page: 6561
End Page: 6565
Language: English
DOI: 10.1073/pnas.1204429109
PROVIDER: scopus
PMCID: PMC3340088
PUBMED: 22493260
Notes: --- - "Export Date: 4 June 2012" - "CODEN: PNASA" - "Source: Scopus"
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MSK Authors
  1. Du H Lam
    3 Lam
  2. Noor I Gammoh
    8 Gammoh
  3. Xuejun Jiang
    83 Jiang
  4. Paul Marks
    147 Marks
  5. Cindy Puente
    4 Puente