The HIV protease inhibitor nelfinavir downregulates Akt phosphorylation by inhibiting proteasomal activity and inducing the unfolded protein response.

The HIV protease inhibitor nelfinavir downregulates Akt phosphorylation by inhibiting proteasomal activity and inducing the unfolded protein response. Research Abstract Details 

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The HIV protease inhibitor nelfinavir downregulates Akt phosphorylation by inhibiting proteasomal activity and inducing the unfolded protein response. Abstract Text:

Anjali K Gupta,Bin Li,George J Cerniglia,Mona S Ahmed,Stephen M Hahn,Amit Maity,

HIV protease inhibitors (HPIs), which have been used to treat HIV patients since the mid 1990s, have been shown to downregulate the phosphatidylinositol 3-kinase (PI3K)-Akt pathway. Because this pathway is frequently activated in human malignancies and associated with resistance to ionizing radiation, we investigated and confirmed that HPIs could radiosensitize cells. However, the mechanism underlying this downregulation was unclear, prompting the investigations in this report. In this paper we show that nelfinavir inhibits proteasome activity. Inhibition of the proteasome leads to endoplasmic reticulum-based stress with accumulation of misfolded proteins, which triggers the unfolded protein response (UPR). As part of the UPR, the alpha subunit of eukaryotic translation initiation factor 2 (eIF2alpha) is phosphorylated, resulting in a decrease in global protein synthesis and induction of the feedback regulator growth arrest and DNA damage-inducible protein (GADD34), which acts as a phosphatase in complex with protein phosphatase 1. This complex dephosphorylates eIF2alpha; however, our data also suggest that this phosphatase activity can dephosphorylate Akt. Furthermore, our data indicate that nelfinavir decreases Akt phosphorylation by triggering this response. These findings may have important implications in understanding how nelfinavir may increase radiation sensitivity and also result in downregulation of the PI3K/Akt pathway.

The HIV protease inhibitor nelfinavir downregulates Akt phosphorylation by inhibiting proteasomal activity and inducing the unfolded protein response. Publishing Authors By Initials

AK Gupta,B Li,GJ Cerniglia,MS Ahmed,SM Hahn,A Maity,

For similar enzymes and coenzymes: enzymes: transferases: phosphotransferases: phosphotransferases (alcohol group acceptor): protein kinases: protein-serine-threonine kinases: proto-oncogene proteins c-akt research abstracts see: enzymes and coenzymes: enzymes: transferases: phosphotransferases: phosphotransferases (alcohol group acceptor): protein kinases: protein-serine-threonine kinases: proto-oncogene proteins c-akt research

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The HIV protease inhibitor nelfinavir downregulates Akt phosphorylation by inhibiting proteasomal activity and inducing the unfolded protein response. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Neoplasia (New York, N.Y.)

VOLUME: 9

Page Numbers: 271-8

Journal Abbreviation:

ISSN: 1476-5586

DAY: 3

MONTH: Apr

YEAR: 2007

The HIV protease inhibitor nelfinavir downregulates Akt phosphorylation by inhibiting proteasomal activity and inducing the unfolded protein response. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 100886622

The HIV protease inhibitor nelfinavir downregulates Akt phosphorylation by inhibiting proteasomal activity and inducing the unfolded protein response. Keywords Mesh Terms:

KEYWORDS: Proto-Oncogene Proteins c-akt

MESH TERMS: metabolism

Chemical & Substance for Abstract: The HIV protease inhibitor nelfinavir downregulates Akt phosphorylation by inhibiting proteasomal activity and inducing the unfolded protein response. Information

Substance Name: Proteasome Endopeptidase Complex

Registry Number: EC 3.4.25.1

Grant and Affiliation Information for The HIV protease inhibitor nelfinavir downregulates Akt phosphorylation by inhibiting proteasomal activity and inducing the unfolded protein response.

AFFILIATION: Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA 19104, USA. gupta@xrt.upenn.edu

Country: Canada

AGENCY: United States NCI

GRANT: R01CA093638

ACRONYM: CA

MEDLINETA: Neoplasia

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