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

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Role of autophagy in histone deacetylase inhibitor-induced apoptotic and nonapoptotic cell death. / Gammoh, N.; Lam, D.; Puente, C.; Marks, P.A.; Jiang, X.; Ganley, I.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 17, 24.04.2012, p. 6561-6565.

Research output: Contribution to journalArticle

Harvard

Gammoh, N, Lam, D, Puente, C, Marks, PA, Jiang, X & Ganley, I 2012, 'Role of autophagy in histone deacetylase inhibitor-induced apoptotic and nonapoptotic cell death' Proceedings of the National Academy of Sciences of the United States of America, vol 109, no. 17, pp. 6561-6565.

APA

Gammoh, N., Lam, D., Puente, C., Marks, P. A., Jiang, X., & Ganley, I. (2012). Role of autophagy in histone deacetylase inhibitor-induced apoptotic and nonapoptotic cell death. Proceedings of the National Academy of Sciences of the United States of America, 109(17), 6561-6565doi: 10.1073/pnas.1204429109

Vancouver

Gammoh N, Lam D, Puente C, Marks PA, Jiang X, Ganley I. Role of autophagy in histone deacetylase inhibitor-induced apoptotic and nonapoptotic cell death. Proceedings of the National Academy of Sciences of the United States of America. 2012 Apr 24;109(17):6561-6565.

Author

Gammoh, N.; Lam, D.; Puente, C.; Marks, P.A.; Jiang, X.; Ganley, I. / Role of autophagy in histone deacetylase inhibitor-induced apoptotic and nonapoptotic cell death.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 17, 24.04.2012, p. 6561-6565.

Research output: Contribution to journalArticle

Bibtex - Download

@article{168992cf32924f9ba01260de0c1f467e,
title = "Role of autophagy in histone deacetylase inhibitor-induced apoptotic and nonapoptotic cell death",
author = "N. Gammoh and D. Lam and C. Puente and P.A. Marks and X. Jiang and I. Ganley",
year = "2012",
volume = "109",
number = "17",
pages = "6561--6565",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Role of autophagy in histone deacetylase inhibitor-induced apoptotic and nonapoptotic cell death

A1 - Gammoh,N.

A1 - Lam,D.

A1 - Puente,C.

A1 - Marks,P.A.

A1 - Jiang,X.

A1 - Ganley,I.

AU - Gammoh,N.

AU - Lam,D.

AU - Puente,C.

AU - Marks,P.A.

AU - Jiang,X.

AU - Ganley,I.

PY - 2012/4/24

Y1 - 2012/4/24

N2 - 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.

AB - 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.

U2 - 10.1073/pnas.1204429109

DO - 10.1073/pnas.1204429109

M1 - Article

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 17

VL - 109

SP - 6561

EP - 6565

ER -

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