The dual targeting of insulin and insulin-like growth factor 1 receptor enhances the mTOR inhibitor-mediated antitumor efficacy in hepatocellular carcinoma
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Claudia Pivonello1, Mariarosaria Negri2, Maria Cristina De Martino1, Maria Napolitano3, Cristina de Angelis2, Donatella Paola Provvisiero2, Gaia Cuomo4, Renata Simona Auriemma2, Chiara Simeoli1, Francesco Izzo5, Annamaria Colao1, Leo J. Hofland6, Rosario Pivonello1
1Dipartimento di Medicina Clinica e Chirurgia, Università “Federico II” di Napoli, Naples, Italy
2IOS & Coleman Medicina Futura Medical Center, Centro Direzionale, Naples, Italy
3Immunology Oncology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione Giovanni Pascale” (IRCCS), Naples, Italy
4IRCCS Fondazione SDN, Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione Giovanni Pascale” (IRCCS), Naples, Italy
5Hepatobiliary Surgery Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione Giovanni Pascale” (IRCCS), Naples, Italy
6Department of Internal Medicine, Division of Endocrinology, Erasmus MC, Rotterdam, The Netherlands
Rosario Pivonello, e-mail: email@example.com
Keywords: HCC, IGF1R, mTOR, OSI-906
Received: August 19, 2015 Accepted: December 26, 2015 Published: January 07, 2016
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.
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