The AXL receptor tyrosine kinase is overexpressed and active in various cancer types including thyroid carcinoma, and several preclinical studies suggest that targeting AXL is an effective therapeutical strategy in AXL-positive cancers. Heat shock protein 90 (HSP90) acts as a molecular chaperone to regulate the conformation, activation, function and stability of many cancer-related kinases. Inhibition of HSP90 by geldanamycin and its derivative 17-Allyl-Ammino-17-demethoxygeldanamycin (17-AAG), leads to simultaneous combinatorial depletion of a wide range of HSP90 client proteins through the induction of their misfolding and proteasome-mediated degradation. The Quality control E3 ligase CHIP ubiquitinates misfolded proteins and favours their degradation. Here we show that treatment of AXL-expressing thyroid cancer cells with 17-AAG induces its proteasome-mediated degradation. Specifically, 17-AAG induces the down-regulation of the fully glycosilated, mature form of the receptor that is exposed on the plasmamembrane and responds to ligand stimulation. Degradation is preceded by AXL ubiquitination by CHIP. Endogenous and overexpressed AXL protein co-immunoprecipitated with CHIP and HSP90, and this complex is modified by 17-AAG treatment. By using different AXL mutants and AXL small molecule inhibitors, we demonstrate that AXL sensitivity to 17-AAG requires AXL kinase domain, but is not dependent on AXL kinase activity. Overall our data elucidate the biological basis of AXL downregulation by HSP 90 inhibition and suggest that Hsp90 inhibition could be effective in treating AXL expressing thyroid cancer.

Therapeutic strategies to target the receptor tyrosine kinase AXL in thyroid cancer

GUIDA, TERESA;VISCIANO, CARLA;LIOTTI, FEDERICA;CARLOMAGNO, Francesca;MELILLO, ROSA MARINA
2012

Abstract

The AXL receptor tyrosine kinase is overexpressed and active in various cancer types including thyroid carcinoma, and several preclinical studies suggest that targeting AXL is an effective therapeutical strategy in AXL-positive cancers. Heat shock protein 90 (HSP90) acts as a molecular chaperone to regulate the conformation, activation, function and stability of many cancer-related kinases. Inhibition of HSP90 by geldanamycin and its derivative 17-Allyl-Ammino-17-demethoxygeldanamycin (17-AAG), leads to simultaneous combinatorial depletion of a wide range of HSP90 client proteins through the induction of their misfolding and proteasome-mediated degradation. The Quality control E3 ligase CHIP ubiquitinates misfolded proteins and favours their degradation. Here we show that treatment of AXL-expressing thyroid cancer cells with 17-AAG induces its proteasome-mediated degradation. Specifically, 17-AAG induces the down-regulation of the fully glycosilated, mature form of the receptor that is exposed on the plasmamembrane and responds to ligand stimulation. Degradation is preceded by AXL ubiquitination by CHIP. Endogenous and overexpressed AXL protein co-immunoprecipitated with CHIP and HSP90, and this complex is modified by 17-AAG treatment. By using different AXL mutants and AXL small molecule inhibitors, we demonstrate that AXL sensitivity to 17-AAG requires AXL kinase domain, but is not dependent on AXL kinase activity. Overall our data elucidate the biological basis of AXL downregulation by HSP 90 inhibition and suggest that Hsp90 inhibition could be effective in treating AXL expressing thyroid cancer.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11588/598233
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