title: The prolyl peptidases PRCP/PREP regulate IRS-1 stability critical for rapamycin-induced feedback activation of PI3K and AKT.
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.
authors.affiliation: From the Department of Anatomy and Cell Biology, Rush University Medical Center, Chicago, Illinois 60612, lduan@rush.edu.
authors.forename: Lei
authors.initials: L
authors.lastname: Duan
authors.affiliation: the Laboratory of Cancer Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.
authors.forename: Guoguang
authors.initials: G
authors.lastname: Ying
authors.affiliation: From the Department of Anatomy and Cell Biology, Rush University Medical Center, Chicago, Illinois 60612.
authors.forename: Brian
authors.initials: B
authors.lastname: Danzer
authors.affiliation: From the Department of Anatomy and Cell Biology, Rush University Medical Center, Chicago, Illinois 60612.
authors.forename: Ricardo E
authors.initials: RE
authors.lastname: Perez
authors.affiliation: the Department of Pharmacology, University of Mississippi, University, Mississippi 38677, and.
authors.forename: Zia
authors.initials: Z
authors.lastname: Shariat-Madar
authors.affiliation: US Biomarkers, Inc., Buffalo Grove, Illinois 60089-6726 victor@usbiomarkers.com.
authors.forename: Victor V
authors.initials: VV
authors.lastname: Levenson
authors.affiliation: From the Department of Anatomy and Cell Biology, Rush University Medical Center, Chicago, Illinois 60612, Carl_Maki@rush.edu.
authors.forename: Carl G
authors.initials: CG
authors.lastname: Maki
mesh_terms: D001483:Base Sequence; D002268:Carboxypeptidases / Q000378:metabolism*; D045744:Cell Line, Tumor; D017931:DNA Primers; D004789:Enzyme Activation; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000085822:Prolyl Oligopeptidases; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology*
chemical_list: D002268:Carboxypeptidases; D017931:DNA Primers; D055504:Insulin Receptor Substrate Proteins; D019869:Phosphatidylinositol 3-Kinases; D000085822:Prolyl Oligopeptidases; D051057:Proto-Oncogene Proteins c-akt; D012697:Serine Endopeptidases; D020123:Sirolimus; C526292:IRS1 protein, human; C022448:lysosomal Pro-X carboxypeptidase; C000705287:PREPL protein, human
keywords: Akt PKB; Apoptosis; Cancer Therapy; Cell Death; Cell Signaling; Mammalian Target of Rapamycin (mTOR); Phosphatidylinositide 3-Kinase (PI 3-kinase)