The Prolyl Peptidases PRCP/PREP Regulate IRS-1 Stability Critical for Rapamycin-induced Feedback Activation of PI3K and AKT

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. Background: Prolylcarboxypeptidase (PRCP) and prolyl endopeptidase (PREP) regulate proliferation and survival of breast cancer cells. Results: PRCP and PREP regulate IRS-1 stability and PI3K/AKT activation in pancreatic cancer cells. Depletion/inhibition of PRCP/PREP suppresses rapamycin-induced activation of PI3K/AKT with consequent additive/synergistic cytotoxicity. Conclusion: PRCP and PREP regulate IRS-1 stability and PI3K/AKT activation in pancreatic cancer. Significance: Prolyl peptidases are potential therapeutic targets in pancreatic cancer.