Parathyroid hormone-related protein induces cell survival in human renal cell carcinoma through the PI3K Akt pathway: evidence for a critical role for integrin-linked kinase and nuclear factor kappa B

Abdelali Agouni, Carole Sourbier, Sabrina Danilin, Sylvie Rothhut, Véronique Lindner, Didier Jacqmin, Jean-Jacques Helwig, Hervé Lang, Thierry Massfelder

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

We have recently shown that parathyroid hormone-related protein (PTHrP), a cytokine-like polyprotein, is critical for human renal cell carcinoma (RCC) growth by inhibiting tumor cell apoptosis. Here, we have explored mechanisms by which PTHrP controls tumor cell survival. Using specific inhibitors of phosphoinositide 3-kinase (PI3K) and depletion of Akt kinase by RNA interference, we established that PTHrP is one of the main factor involved in the constitutive activation of this pathway in human RCC, independently of von Hippel-Lindau (VHL) tumor suppressor gene expression. Interestingly, PTHrP induced phosphorylation of Akt at S473 but had no influence on phosphorylation at T308. Through transfection with integrin-linked kinase (ILK) constructs and RNA interference, we provide evidence that ILK is involved in human RCC cell survival. PTHrP activates ILK which then acts as a phosphoinositide-dependent kinase (PDK)-2 or a facilitator protein to phosphorylate Akt at S473. Among other kinases tested, only ILK was shown to exert this function in RCC. Using specific inhibitors, western blot and transcription assay, we identified nuclear factor kappa B (NF-kappaB) as the downstream Akt target regulated by PTHrP. Since RCC remains refractory to current therapies, our results establish that the PI3K/ILK/Akt/NF-kappaB axis is a promising target for therapeutic intervention.
Original languageEnglish
Pages (from-to)1893-1901
Number of pages9
JournalCarcinogenesis
Volume28
Issue number9
DOIs
Publication statusPublished - 2007

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Parathyroid Hormone-Related Protein
1-Phosphatidylinositol 4-Kinase
NF-kappa B
Renal Cell Carcinoma
Cell Survival
RNA Interference
Phosphotransferases
Phosphorylation
Polyproteins
Tumor Suppressor Genes
Transfection
integrin-linked kinase
Neoplasms
Western Blotting
Apoptosis
Cytokines
Gene Expression
Therapeutics
Growth
Proteins

Keywords

  • 1-Phosphatidylinositol 3-Kinase
  • Apoptosis
  • Carcinoma, Renal Cell
  • Carrier Proteins
  • Cell Division
  • Cell Line, Tumor
  • Cell Survival
  • Humans
  • Kidney Neoplasms
  • NF-kappa B
  • Parathyroid Hormone-Related Protein
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • RNA Interference
  • Transfection

Cite this

Parathyroid hormone-related protein induces cell survival in human renal cell carcinoma through the PI3K Akt pathway : evidence for a critical role for integrin-linked kinase and nuclear factor kappa B. / Agouni, Abdelali; Sourbier, Carole; Danilin, Sabrina; Rothhut, Sylvie; Lindner, Véronique; Jacqmin, Didier; Helwig, Jean-Jacques; Lang, Hervé; Massfelder, Thierry.

In: Carcinogenesis, Vol. 28, No. 9, 2007, p. 1893-1901.

Research output: Contribution to journalArticle

Agouni, Abdelali ; Sourbier, Carole ; Danilin, Sabrina ; Rothhut, Sylvie ; Lindner, Véronique ; Jacqmin, Didier ; Helwig, Jean-Jacques ; Lang, Hervé ; Massfelder, Thierry. / Parathyroid hormone-related protein induces cell survival in human renal cell carcinoma through the PI3K Akt pathway : evidence for a critical role for integrin-linked kinase and nuclear factor kappa B. In: Carcinogenesis. 2007 ; Vol. 28, No. 9. pp. 1893-1901.
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abstract = "We have recently shown that parathyroid hormone-related protein (PTHrP), a cytokine-like polyprotein, is critical for human renal cell carcinoma (RCC) growth by inhibiting tumor cell apoptosis. Here, we have explored mechanisms by which PTHrP controls tumor cell survival. Using specific inhibitors of phosphoinositide 3-kinase (PI3K) and depletion of Akt kinase by RNA interference, we established that PTHrP is one of the main factor involved in the constitutive activation of this pathway in human RCC, independently of von Hippel-Lindau (VHL) tumor suppressor gene expression. Interestingly, PTHrP induced phosphorylation of Akt at S473 but had no influence on phosphorylation at T308. Through transfection with integrin-linked kinase (ILK) constructs and RNA interference, we provide evidence that ILK is involved in human RCC cell survival. PTHrP activates ILK which then acts as a phosphoinositide-dependent kinase (PDK)-2 or a facilitator protein to phosphorylate Akt at S473. Among other kinases tested, only ILK was shown to exert this function in RCC. Using specific inhibitors, western blot and transcription assay, we identified nuclear factor kappa B (NF-kappaB) as the downstream Akt target regulated by PTHrP. Since RCC remains refractory to current therapies, our results establish that the PI3K/ILK/Akt/NF-kappaB axis is a promising target for therapeutic intervention.",
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T2 - evidence for a critical role for integrin-linked kinase and nuclear factor kappa B

AU - Agouni, Abdelali

AU - Sourbier, Carole

AU - Danilin, Sabrina

AU - Rothhut, Sylvie

AU - Lindner, Véronique

AU - Jacqmin, Didier

AU - Helwig, Jean-Jacques

AU - Lang, Hervé

AU - Massfelder, Thierry

PY - 2007

Y1 - 2007

N2 - We have recently shown that parathyroid hormone-related protein (PTHrP), a cytokine-like polyprotein, is critical for human renal cell carcinoma (RCC) growth by inhibiting tumor cell apoptosis. Here, we have explored mechanisms by which PTHrP controls tumor cell survival. Using specific inhibitors of phosphoinositide 3-kinase (PI3K) and depletion of Akt kinase by RNA interference, we established that PTHrP is one of the main factor involved in the constitutive activation of this pathway in human RCC, independently of von Hippel-Lindau (VHL) tumor suppressor gene expression. Interestingly, PTHrP induced phosphorylation of Akt at S473 but had no influence on phosphorylation at T308. Through transfection with integrin-linked kinase (ILK) constructs and RNA interference, we provide evidence that ILK is involved in human RCC cell survival. PTHrP activates ILK which then acts as a phosphoinositide-dependent kinase (PDK)-2 or a facilitator protein to phosphorylate Akt at S473. Among other kinases tested, only ILK was shown to exert this function in RCC. Using specific inhibitors, western blot and transcription assay, we identified nuclear factor kappa B (NF-kappaB) as the downstream Akt target regulated by PTHrP. Since RCC remains refractory to current therapies, our results establish that the PI3K/ILK/Akt/NF-kappaB axis is a promising target for therapeutic intervention.

AB - We have recently shown that parathyroid hormone-related protein (PTHrP), a cytokine-like polyprotein, is critical for human renal cell carcinoma (RCC) growth by inhibiting tumor cell apoptosis. Here, we have explored mechanisms by which PTHrP controls tumor cell survival. Using specific inhibitors of phosphoinositide 3-kinase (PI3K) and depletion of Akt kinase by RNA interference, we established that PTHrP is one of the main factor involved in the constitutive activation of this pathway in human RCC, independently of von Hippel-Lindau (VHL) tumor suppressor gene expression. Interestingly, PTHrP induced phosphorylation of Akt at S473 but had no influence on phosphorylation at T308. Through transfection with integrin-linked kinase (ILK) constructs and RNA interference, we provide evidence that ILK is involved in human RCC cell survival. PTHrP activates ILK which then acts as a phosphoinositide-dependent kinase (PDK)-2 or a facilitator protein to phosphorylate Akt at S473. Among other kinases tested, only ILK was shown to exert this function in RCC. Using specific inhibitors, western blot and transcription assay, we identified nuclear factor kappa B (NF-kappaB) as the downstream Akt target regulated by PTHrP. Since RCC remains refractory to current therapies, our results establish that the PI3K/ILK/Akt/NF-kappaB axis is a promising target for therapeutic intervention.

KW - 1-Phosphatidylinositol 3-Kinase

KW - Apoptosis

KW - Carcinoma, Renal Cell

KW - Carrier Proteins

KW - Cell Division

KW - Cell Line, Tumor

KW - Cell Survival

KW - Humans

KW - Kidney Neoplasms

KW - NF-kappa B

KW - Parathyroid Hormone-Related Protein

KW - Protein-Serine-Threonine Kinases

KW - Proto-Oncogene Proteins c-akt

KW - RNA Interference

KW - Transfection

U2 - 10.1093/carcin/bgm106

DO - 10.1093/carcin/bgm106

M3 - Article

VL - 28

SP - 1893

EP - 1901

JO - Carcinogenesis

JF - Carcinogenesis

SN - 0143-3334

IS - 9

ER -