Mammalian target of rapamycin and S6 kinase 1 positively regulate 6-thioguanine-induced autophagy.

Mammalian target of rapamycin and S6 kinase 1 positively regulate 6-thioguanine-induced autophagy. Research Abstract Details 

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Mammalian target of rapamycin and S6 kinase 1 positively regulate 6-thioguanine-induced autophagy. Abstract Text:

Xuehuo Zeng,Timothy J Kinsella,Xuehuo Zeng,Timothy J Kinsella,

DNA mismatch repair (MMR) ensures the fidelity of DNA replication and is required for activation of cell cycle arrest and apoptosis in response to certain classes of DNA damage. We recently reported that MMR is also implicated in initiation of an autophagic response after MMR processing of 6-thioguanine (6-TG). It is now generally believed that autophagy is negatively controlled by mammalian target of rapamycin (mTOR) activity. To determine whether mTOR is involved in 6-TG-induced autophagy, we used rapamycin, a potential anticancer agent, to inhibit mTOR activity. Surprisingly, we find that rapamycin cotreatment inhibits 6-TG-induced autophagy in MMR-proficient human colorectal cancer HCT116 (MLH1(+)) and HT29 cells as measured by LC3 immunoblotting, GFP-LC3 relocalization, and acridine orange staining. Consistently, short interfering RNA silencing of the 70-kDa ribosomal S6 kinase 1 (S6K1), the downstream effector of mTOR, markedly reduces 6-TG-induced autophagy. Furthermore, we show that inhibition of mTOR by rapamycin induces the activation of Akt as shown by increased Akt phosphorylation at Ser(473) and the inhibition of 6-TG-induced apoptosis and cell death. Activated Akt is a well-known inhibitor of autophagy. In conclusion, our data indicate that mTOR-S6K1 positively regulates autophagy after MMR processing of 6-TG probably through its negative feedback inhibition of Akt.

Mammalian target of rapamycin and S6 kinase 1 positively regulate 6-thioguanine-induced autophagy. Publishing Authors By Initials

X Zeng,TJ Kinsella,X Zeng,TJ Kinsella,

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Mammalian target of rapamycin and S6 kinase 1 positively regulate 6-thioguanine-induced autophagy. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Cancer research

VOLUME: 68

Page Numbers: 2384-90

Journal Abbreviation: Cancer Res.

ISSN: 1538-7445

DAY: 1

MONTH: Apr

YEAR: 2008

Mammalian target of rapamycin and S6 kinase 1 positively regulate 6-thioguanine-induced autophagy. Information

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LANGUAGE: eng

NlmUniqueID: 2984705

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Grant and Affiliation Information for Mammalian target of rapamycin and S6 kinase 1 positively regulate 6-thioguanine-induced autophagy.

AFFILIATION: Department of Radiation Oncology, Case Western Reserve University, Case Comprehensive Cancer Center/University Hospitals Case Medical Center, Cleveland, OH 44106-6068, USA.

Country: United States

AGENCY: United States NCI

GRANT: CA50595

ACRONYM: CA

MEDLINETA: Cancer Res

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