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J Biol Chem. 2014 Aug 1;289(31):21694-705. doi: 10.1074/jbc.M114.550038. Epub 2014 Jun 16.

The prolyl peptidases PRCP/PREP regulate IRS-1 stability critical for rapamycin-induced feedback activation of PI3K and AKT.

Author information

1
From the Department of Anatomy and Cell Biology, Rush University Medical Center, Chicago, Illinois 60612, lduan@rush.edu.
2
the Laboratory of Cancer Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.
3
From the Department of Anatomy and Cell Biology, Rush University Medical Center, Chicago, Illinois 60612.
4
the Department of Pharmacology, University of Mississippi, University, Mississippi 38677, and.
5
US Biomarkers, Inc., Buffalo Grove, Illinois 60089-6726 victor@usbiomarkers.com.
6
From the Department of Anatomy and Cell Biology, Rush University Medical Center, Chicago, Illinois 60612, Carl_Maki@rush.edu.

Abstract

The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT)/mammalian target of rapamycin (mTOR) pathway conveys signals from receptor tyrosine kinases (RTKs) to regulate cell metabolism, proliferation, survival, and motility. Previously we found that prolylcarboxypeptidase (PRCP) regulate proliferation and survival in breast cancer cells. In this study, we found that PRCP and the related family member prolylendopeptidase (PREP) are essential for proliferation and survival of pancreatic cancer cells. Depletion/inhibition of PRCP and PREP-induced serine phosphorylation and degradation of IRS-1, leading to inactivation of the cellular PI3K and AKT. Notably, depletion/inhibition of PRCP/PREP destabilized IRS-1 in the cells treated with rapamycin, blocking the feedback activation PI3K/AKT. Consequently, inhibition of PRCP/PREP enhanced rapamycin-induced cytotoxicity. Thus, we have identified PRCP and PREP as a stabilizer of IRS-1 which is critical for PI3K/AKT/mTOR signaling in pancreatic cancer cells.

KEYWORDS:

Akt PKB; Apoptosis; Cancer Therapy; Cell Death; Cell Signaling; Mammalian Target of Rapamycin (mTOR); Phosphatidylinositide 3-Kinase (PI 3-kinase)

PMID:
24936056
PMCID:
PMC4118128
DOI:
10.1074/jbc.M114.550038
[Indexed for MEDLINE]
Free PMC Article
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