The dual targeting of insulin and insulin-like growth factor 1 receptor enhances the mTOR inhibitor-mediated antitumor efficacy in hepatocellular carcinoma

C. Pivonello, Mariarosaria Negri, Maria Cristina De Martino, Maria Napolitano, Cristina de Angelis, Donatella Paola Provvisiero, Gaia Cuomo, R. S. Auriemma, Chiara Simeoli, Francesco Izzo, A. Colao, L. J. Hofland, Rosario Pivonello

Research output: Contribution to journalArticle

Abstract

Deregulation of mTOR and IGF pathways is frequent in hepatocellular carcinoma (HCC), thus mTOR and IGF1R represent suitable therapeutic targets in HCC. The aim of this study was to evaluate the effects of mTOR inhibitors (mTORi) and OSI-906, blocker of IGF1R/IR, on HCC cell proliferation, viability, migration and invasion, and alpha-fetoprotein (α-FP) secretion. In HepG2 and HuH-7 we evaluated, the expression of mTOR and IGF pathway components; the effects of Sirolimus, Everolimus, Temsirolimus and OSI-906 on cell proliferation; the effects of Sirolimus, OSI-906, and their combination, on cell secretion, proliferation, viability, cell cycle, apoptosis, invasion and migration. Moreover, intracellular mechanisms underlying these cell functions were evaluated in both cell lines. Our results show that HepG2 and HuH-7 present with the same mRNA expression profile with high levels of IGF2. OSI-906 inhibited cell proliferation at high concentration, while mTORi suppressed cell proliferation in a dose-time dependent manner in both cell lines. The co-treatment showed an additive inhibitory effect on cell proliferation and viability. This effect was not related to induction of apoptosis, but to G0/G1 phase block. Moreover, the co-treatment prevented the Sirolimus-induced AKT activation as escape mechanism. Both agents demonstrated to be differently effective in inhibiting α-FP secretion. Sirolimus, OSI-906, and their combination, blocked cell migration and invasion in HuH-7. These findings indicate that, co-targeting of IGF1R/IR and mTOR pathways could be a novel therapeutic approach in the management of HCC, in order to maximize antitumoral effect and to prevent the early development of resistance mechanisms.

Original languageEnglish
Pages (from-to)9718-9731
Number of pages14
JournalOncotarget
Volume7
Issue number9
DOIs
Publication statusPublished - 2016

Fingerprint

Somatomedin Receptors
Hepatocellular Carcinoma
Cell Proliferation
Sirolimus
Insulin
Cell Movement
Cell Survival
Apoptosis
Cell Line
Cell Cycle Resting Phase
alpha-Fetoproteins
G1 Phase
Cell Cycle
3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol
Messenger RNA
Therapeutics

Keywords

  • HCC
  • IGF1R
  • MTOR
  • OSI-906

ASJC Scopus subject areas

  • Oncology

Cite this

The dual targeting of insulin and insulin-like growth factor 1 receptor enhances the mTOR inhibitor-mediated antitumor efficacy in hepatocellular carcinoma. / Pivonello, C.; Negri, Mariarosaria; De Martino, Maria Cristina; Napolitano, Maria; de Angelis, Cristina; Provvisiero, Donatella Paola; Cuomo, Gaia; Auriemma, R. S.; Simeoli, Chiara; Izzo, Francesco; Colao, A.; Hofland, L. J.; Pivonello, Rosario.

In: Oncotarget, Vol. 7, No. 9, 2016, p. 9718-9731.

Research output: Contribution to journalArticle

Pivonello, C, Negri, M, De Martino, MC, Napolitano, M, de Angelis, C, Provvisiero, DP, Cuomo, G, Auriemma, RS, Simeoli, C, Izzo, F, Colao, A, Hofland, LJ & Pivonello, R 2016, 'The dual targeting of insulin and insulin-like growth factor 1 receptor enhances the mTOR inhibitor-mediated antitumor efficacy in hepatocellular carcinoma', Oncotarget, vol. 7, no. 9, pp. 9718-9731. https://doi.org/10.18632/oncotarget.6836
Pivonello, C. ; Negri, Mariarosaria ; De Martino, Maria Cristina ; Napolitano, Maria ; de Angelis, Cristina ; Provvisiero, Donatella Paola ; Cuomo, Gaia ; Auriemma, R. S. ; Simeoli, Chiara ; Izzo, Francesco ; Colao, A. ; Hofland, L. J. ; Pivonello, Rosario. / The dual targeting of insulin and insulin-like growth factor 1 receptor enhances the mTOR inhibitor-mediated antitumor efficacy in hepatocellular carcinoma. In: Oncotarget. 2016 ; Vol. 7, No. 9. pp. 9718-9731.
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