Carcinogenesis Advance Access originally published online on April 29, 2007
Carcinogenesis 2007 28(9):1893-1901; doi:10.1093/carcin/bgm106
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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
1 INSERM U727, Section of Renal Pharmacology and Physiopathology, School of Medicine, University Louis Pasteur, Strasbourg 67085, France
2 Department of Pathology
3 Department of Urology, Hôpitaux Universitaires de Strasbourg, Strasbourg 67091, France
* To whom correspondence should be addressed. Tel: +33 3 90 24 34 56; Fax: +33 3 90 24 34 59; Email: thierry.massfelder{at}medecine.u-strasbg.fr
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-
B) as the downstream Akt target regulated by PTHrP. Since RCC remains refractory to current therapies, our results establish that the PI3K/ILK/Akt/NF-B axis is a promising target for therapeutic intervention.
Abbreviations: Ab, antibody; CRCC, conventional renal cell carcinoma; FACS, fluorescence-activated cell sorting; FKHR, forkhead transcription factor; GSK-3, glycogen synthase kinase-3; ILK, integrin-linked kinase; mTOR, mammalian target of rapamycine; NF-B, nuclear factor kappa B; PDK, phosphoinositide-dependent kinase; PKA, protein kinase A; PKC, protein kinase C; PI3K, phosphoinositide 3-kinase; PTHrP, parathyroid hormone-related protein; RCC, renal cell carcinoma; siRNA, small interfering RNA; TUNEL, Tdt-dependent dUTP-biotin nick end labeling; VHL, von Hippel-Lindau
Received January 29, 2007; revised April 2, 2007; accepted April 24, 2007.
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