Blockade of IGF-1 receptor tyrosine kinase has antineoplastic effects in hepatocellular carcinoma cells

Regulation of survivin expression by IGF-1/mTOR signaling

“…In this context, much attention has been devoted towards elucidating the molecular requirements of survivin gene transcription, but recent evidence points to additional, non-transcriptional mechanisms controlling survivin levels in tumor cells (Altieri, 2003). One such pathway is centered on IGF-1 ligation to its cognate membrane receptor, which has been shown to increase survivin expression in prostate (Zhang et al, 2005), myeloma (Stromberg et al, 2006) and liver (Hopfner et al, 2006) tumor cell types, even though the underlying mechanism(s) of this response had remained elusive. As now reported here, this pathway depends on IGF-IR transforming potential (Sell et al, 1994), does not involve changes in cell cycle distribution and is not associated with de novo survivin promoter activity or increased survivin protein stability.…”

“…As a multifaceted mTOR effector, survivin appears ideally positioned to contribute to these responses, by favoring mitotic progression, resistance to apoptosis and increased cellular adaptation to stress (Altieri, 2003). Conversely, targeted inhibition of IGF-1/Akt/mTOR couples to cell cycle arrest and induction of apoptosis, which may be contributed by acute loss of survivin levels (Decker et al, 2003;Hopfner et al, 2006;Stromberg et al, 2006), Forkheadmediated transcription of the cyclin-dependent kinase inhibitor p27 (Wullschleger et al, 2006) and activation of p53-dependent apoptosis (Levine et al, 2006).…”

Reactivation of the insulin-like growth factor-II signaling pathway in human hepatocellular carcinoma

“…Antitumorigenic effects of some inhibitors on HCC cells have been demonstrated. The application of NVP-AEW541 [113] and picropodophyllin (Nussbaum et al, unpublished data) was shown to reduce tumor cell proliferation and increase apoptosis. Equally, IGF-Ⅱ induced tumor cell motility was reduced by picropodophyllin (Nussbaum et al, unpublished data).…”

The type 1 insulin-like growth factor receptor signalling system and targeted tyrosine kinase inhibition in cancer

“…65 As expected for a specific IGF1R kinase inhibitor, NVP-AEW541 abrogated IGF1-mediated survival, inhibited the proliferation of cultured tumour cell lines by inducing apoptosis and cell cycle arrest in vitro, and significantly inhibited the growth of tumour xenografts in vivo. 65,76,77,[79][80][81][82][83][84][85][86][87][88][89] Accumulating evidence suggests that NVP-AEW541 represents a potential therapeutic strategy for the treatment of tumour types in which IGF1R-mediated signalling is required for driving/ survival.…”