Adrenocortical carcinomas (ACCs) overexpress insulin-like growth factor 2 (IGF2), that drives a proliferative autocrine loop by binding to IGF1R and IR, but IGF1R/IR-targeted therapies failed in ACC patients. The cytoskeleton actin-binding protein filamin A (FLNA) impairs IR signalling in melanoma cells. Aims of this study were to test FLNA involvement in regulating IGF1R and IR responsiveness to both IGF2 and inhibitors in ACC. In ACC cells H295R and SW13 and primary cultures (1ACC, 4 adenomas) we found that IGF1R and IR interacted with FLNA, and FLNA silencing increased IGF1R and reduced IR expression, with a downstream effect of increased cell proliferation and ERK phosphorylation. In addition, FLNA knockdown potentiated antiproliferative effects of IGF1R/IR inhibitor Linsitinib and IGF1R inhibitor NVP-ADW742 in H295R. Finally, Western blot showed lower FLNA expression in ACCs (n = 10) than in ACAs (n = 10) and an inverse correlation of FLNA/IGF1R ratio with ERK phosphorylation in ACCs only. In conclusion, we demonstrated that low FLNA levels enhance both IGF2 proliferative effects and IGF1R/IR inhibitors efficacy in ACC cells, suggesting FLNA as a new factor influencing tumor clinical behavior and the response to the therapy with IGF1R/IR-targeted drugs.

The cytoskeleton actin binding protein filamin A impairs both IGF2 mitogenic effects and the efficacy of IGF1R inhibitors in adrenocortical cancer cells / R. Catalano, E. Giardino, D. Treppiedi, F. Mangili, V. Morelli, F.M. Elli, A.L. Serban, M. Luconi, M. Mannelli, A. Spada, M. Arosio, G. Mantovani, E. Peverelli. - In: CANCER LETTERS. - ISSN 0304-3835. - 497(2021 Jan), pp. 77-88. [10.1016/j.canlet.2020.10.022]

The cytoskeleton actin binding protein filamin A impairs both IGF2 mitogenic effects and the efficacy of IGF1R inhibitors in adrenocortical cancer cells

R. Catalano;D. Treppiedi;F. Mangili;F.M. Elli;M. Arosio;G. Mantovani
;
E. Peverelli
2021

Abstract

Adrenocortical carcinomas (ACCs) overexpress insulin-like growth factor 2 (IGF2), that drives a proliferative autocrine loop by binding to IGF1R and IR, but IGF1R/IR-targeted therapies failed in ACC patients. The cytoskeleton actin-binding protein filamin A (FLNA) impairs IR signalling in melanoma cells. Aims of this study were to test FLNA involvement in regulating IGF1R and IR responsiveness to both IGF2 and inhibitors in ACC. In ACC cells H295R and SW13 and primary cultures (1ACC, 4 adenomas) we found that IGF1R and IR interacted with FLNA, and FLNA silencing increased IGF1R and reduced IR expression, with a downstream effect of increased cell proliferation and ERK phosphorylation. In addition, FLNA knockdown potentiated antiproliferative effects of IGF1R/IR inhibitor Linsitinib and IGF1R inhibitor NVP-ADW742 in H295R. Finally, Western blot showed lower FLNA expression in ACCs (n = 10) than in ACAs (n = 10) and an inverse correlation of FLNA/IGF1R ratio with ERK phosphorylation in ACCs only. In conclusion, we demonstrated that low FLNA levels enhance both IGF2 proliferative effects and IGF1R/IR inhibitors efficacy in ACC cells, suggesting FLNA as a new factor influencing tumor clinical behavior and the response to the therapy with IGF1R/IR-targeted drugs.
Adrenocortical carcinoma; Cytoskeleton; Growth factors; Linsitinib; NVP-ADW742
Settore MED/13 - Endocrinologia
16-ott-2020
Article (author)
File in questo prodotto:
File Dimensione Formato  
Catalano R..pdf

accesso riservato

Tipologia: Publisher's version/PDF
Dimensione 6.17 MB
Formato Adobe PDF
6.17 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/785451
Citazioni
  • ???jsp.display-item.citation.pmc??? 2
  • Scopus 2
  • ???jsp.display-item.citation.isi??? 2
social impact