The phosphatase PHLPP1 regulates Akt2, promotes pancreatic cancer cell death, and inhibits tumor formation

Claudia Nitsche, Mouad Edderkaoui, Ryan M. Moore, Guido Eibl, Noriyuki Kasahara, Janet Treger, Paul J. Grippo, Julia Mayerle, Markus M. Lerch, Anna S. Gukovskaya

Research output: Contribution to journalArticle

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Abstract

Background & Aims: The kinase Akt mediates resistance of pancreatic cancer (PaCa) cells to death and is constitutively active (phosphorylated) in cancer cells. Whereas the kinases that activate Akt are well characterized, less is known about phosphatases that dephosporylate and thereby inactivate it. We investigated regulation of Akt activity and cell death by the phosphatases PHLPP1 and PHLPP2 in PaCa cells, mouse models of PaCa, and human pancreatic ductal adenocarcinoma (PDAC). Methods: We measured the effects of PHLPP overexpression or knockdown with small interfering RNAs on Akt activation and cell death. We examined regulation of PHLPPs by growth factors and reactive oxygen species, as well as associations between PHLPPs and tumorigenesis. Results: PHLPP overexpression inactivated Akt, whereas PHLPP knockdown increased phosphorylation of Akt in PaCa cells. Levels of PHLPPs were greatly reduced in human PDAC and in mouse genetic and xenograft models of PaCa. PHLPP activities in PaCa cells were down-regulated by growth factors and Nox4 reduced nicotinamide adenine dinucleotide phosphate oxidase. PHLPP1 selectively dephosphorylated Akt2, whereas PHLPP2 selectively dephosphorylated Akt1. Akt2, but not Akt1, was up-regulated in PDAC, and Akt2 levels correlated with mortality. Consistent with these results, high levels of PHLPP1, which dephosphorylates Akt2 (but not PHLPP2, which dephosphorylates Akt1), correlated with longer survival times of patients with PDAC. In mice, xenograft tumors derived from PaCa cells that overexpress PHLPP1 (but not PHLPP2) had inactivated Akt, greater extent of apoptosis, and smaller size. Conclusions: PHLPP1 has tumor suppressive activity and might represent a therapeutic or diagnostic tool for PDAC.

Original languageEnglish (US)
JournalGastroenterology
Volume142
Issue number2
DOIs
StatePublished - Feb 2012
Externally publishedYes

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Pancreatic Neoplasms
Phosphoric Monoester Hydrolases
Cell Death
Adenocarcinoma
Neoplasms
Heterografts
Intercellular Signaling Peptides and Proteins
Phosphotransferases
Genetic Models
NADP
Small Interfering RNA
Reactive Oxygen Species
Oxidoreductases
Carcinogenesis
Phosphorylation
Apoptosis
Survival
Mortality

Keywords

  • Apoptosis
  • NADPH Oxidase
  • ROS
  • Tumor Progression

ASJC Scopus subject areas

  • Gastroenterology

Cite this

The phosphatase PHLPP1 regulates Akt2, promotes pancreatic cancer cell death, and inhibits tumor formation. / Nitsche, Claudia; Edderkaoui, Mouad; Moore, Ryan M.; Eibl, Guido; Kasahara, Noriyuki; Treger, Janet; Grippo, Paul J.; Mayerle, Julia; Lerch, Markus M.; Gukovskaya, Anna S.

In: Gastroenterology, Vol. 142, No. 2, 02.2012.

Research output: Contribution to journalArticle

Nitsche, C, Edderkaoui, M, Moore, RM, Eibl, G, Kasahara, N, Treger, J, Grippo, PJ, Mayerle, J, Lerch, MM & Gukovskaya, AS 2012, 'The phosphatase PHLPP1 regulates Akt2, promotes pancreatic cancer cell death, and inhibits tumor formation', Gastroenterology, vol. 142, no. 2. https://doi.org/10.1053/j.gastro.2011.10.026
Nitsche, Claudia ; Edderkaoui, Mouad ; Moore, Ryan M. ; Eibl, Guido ; Kasahara, Noriyuki ; Treger, Janet ; Grippo, Paul J. ; Mayerle, Julia ; Lerch, Markus M. ; Gukovskaya, Anna S. / The phosphatase PHLPP1 regulates Akt2, promotes pancreatic cancer cell death, and inhibits tumor formation. In: Gastroenterology. 2012 ; Vol. 142, No. 2.
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abstract = "Background & Aims: The kinase Akt mediates resistance of pancreatic cancer (PaCa) cells to death and is constitutively active (phosphorylated) in cancer cells. Whereas the kinases that activate Akt are well characterized, less is known about phosphatases that dephosporylate and thereby inactivate it. We investigated regulation of Akt activity and cell death by the phosphatases PHLPP1 and PHLPP2 in PaCa cells, mouse models of PaCa, and human pancreatic ductal adenocarcinoma (PDAC). Methods: We measured the effects of PHLPP overexpression or knockdown with small interfering RNAs on Akt activation and cell death. We examined regulation of PHLPPs by growth factors and reactive oxygen species, as well as associations between PHLPPs and tumorigenesis. Results: PHLPP overexpression inactivated Akt, whereas PHLPP knockdown increased phosphorylation of Akt in PaCa cells. Levels of PHLPPs were greatly reduced in human PDAC and in mouse genetic and xenograft models of PaCa. PHLPP activities in PaCa cells were down-regulated by growth factors and Nox4 reduced nicotinamide adenine dinucleotide phosphate oxidase. PHLPP1 selectively dephosphorylated Akt2, whereas PHLPP2 selectively dephosphorylated Akt1. Akt2, but not Akt1, was up-regulated in PDAC, and Akt2 levels correlated with mortality. Consistent with these results, high levels of PHLPP1, which dephosphorylates Akt2 (but not PHLPP2, which dephosphorylates Akt1), correlated with longer survival times of patients with PDAC. In mice, xenograft tumors derived from PaCa cells that overexpress PHLPP1 (but not PHLPP2) had inactivated Akt, greater extent of apoptosis, and smaller size. Conclusions: PHLPP1 has tumor suppressive activity and might represent a therapeutic or diagnostic tool for PDAC.",
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AU - Nitsche, Claudia

AU - Edderkaoui, Mouad

AU - Moore, Ryan M.

AU - Eibl, Guido

AU - Kasahara, Noriyuki

AU - Treger, Janet

AU - Grippo, Paul J.

AU - Mayerle, Julia

AU - Lerch, Markus M.

AU - Gukovskaya, Anna S.

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AB - Background & Aims: The kinase Akt mediates resistance of pancreatic cancer (PaCa) cells to death and is constitutively active (phosphorylated) in cancer cells. Whereas the kinases that activate Akt are well characterized, less is known about phosphatases that dephosporylate and thereby inactivate it. We investigated regulation of Akt activity and cell death by the phosphatases PHLPP1 and PHLPP2 in PaCa cells, mouse models of PaCa, and human pancreatic ductal adenocarcinoma (PDAC). Methods: We measured the effects of PHLPP overexpression or knockdown with small interfering RNAs on Akt activation and cell death. We examined regulation of PHLPPs by growth factors and reactive oxygen species, as well as associations between PHLPPs and tumorigenesis. Results: PHLPP overexpression inactivated Akt, whereas PHLPP knockdown increased phosphorylation of Akt in PaCa cells. Levels of PHLPPs were greatly reduced in human PDAC and in mouse genetic and xenograft models of PaCa. PHLPP activities in PaCa cells were down-regulated by growth factors and Nox4 reduced nicotinamide adenine dinucleotide phosphate oxidase. PHLPP1 selectively dephosphorylated Akt2, whereas PHLPP2 selectively dephosphorylated Akt1. Akt2, but not Akt1, was up-regulated in PDAC, and Akt2 levels correlated with mortality. Consistent with these results, high levels of PHLPP1, which dephosphorylates Akt2 (but not PHLPP2, which dephosphorylates Akt1), correlated with longer survival times of patients with PDAC. In mice, xenograft tumors derived from PaCa cells that overexpress PHLPP1 (but not PHLPP2) had inactivated Akt, greater extent of apoptosis, and smaller size. Conclusions: PHLPP1 has tumor suppressive activity and might represent a therapeutic or diagnostic tool for PDAC.

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KW - NADPH Oxidase

KW - ROS

KW - Tumor Progression

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