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Mol Cancer Res. 2015 Dec;13(12):1602-14. doi: 10.1158/1541-7786.MCR-15-0213. Epub 2015 Sep 15.

Differential IKK/NF-κB Activity Is Mediated by TSC2 through mTORC1 in PTEN-Null Prostate Cancer and Tuberous Sclerosis Complex Tumor Cells.

Author information

1
Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland. Dalian Municipal Central Hospital Affiliated of Dalian Medical University, Dalian, Liaoning Province, P.R China.
2
Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland.
3
Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland. Baltimore VA Medical Center, Baltimore, Maryland.
4
Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, P.R. China.
5
Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland. Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland. HDan@som.umaryland.edu.

Abstract

The serine/threonine protein kinase Akt plays a critical role in regulating proliferation, growth, and survival through phosphorylation of different downstream substrates. The mTOR is a key target for Akt to promote tumorigenesis. It has been reported that Akt activates mTOR through phosphorylation and inhibition of the tuberous sclerosis complex (TSC) protein TSC2. Previously, it was demonstrated that mTOR activates IKK/NF-κB signaling by promoting IκB kinase (IKK) activity downstream of Akt in conditions deficient of PTEN. In this study, the mechanistic role of the tumor-suppressor TSC2 was investigated in the regulation of IKK/NF-κB activity in PTEN-null prostate cancer and in TSC2-mutated tumor cells. The results demonstrate that TSC2 inhibits IKK/NF-κB activity downstream of Akt and upstream of mTORC1 in a PTEN-deficient environment. However, TSC2 promotes IKK/NF-κB activity upstream of Akt and mTORC1 in TSC2 mutated tumor cells. These data indicate that TSC2 negatively or positively regulates IKK/NF-κB activity in a context-dependent manner depending on the genetic background.

IMPLICATIONS:

This study provides fundamental insight for understanding the molecular details by which TSC2/mTOR regulates NF-κB signaling in different tumors.

PMID:
26374334
PMCID:
PMC4690470
DOI:
10.1158/1541-7786.MCR-15-0213
[Indexed for MEDLINE]
Free PMC Article

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