The cyclolignan PPP induces activation loop-specific inhibition of tyrosine phosphorylation of the insulin-like growth factor-1 receptor. Link to the phosphatidyl inositol-3 kinase/Akt apoptotic pathway

Picropodophyllin induces downregulation of the insulin-like growth factor 1 receptor: potential mechanistic involvement of Mdm2 and β-arrestin1

“…This leads to a rapid and substantial inhibition of Akt phosphorylation, massive apoptosis and tumor regression The accurate intramolecular mechanism of PPP is still unknown, but previous data indicated that it may abrogate phosphorylation of tyrosine residue 1136 in the activation loop of the kinase (Vasilcanu et al, 2004). The present study adds a new aspect on the mechanism of action of PPP, demonstrating that it besides inhibiting IGF-1R phosphorylation induces ligand-independent degradation of the receptor.…”

“…Thus, the protective effect of b-arrestin1 knockdown on PPPinduced IGF-1R downregulation correlates well with its protective effect on cell survival. The PPP-induced apoptotic effect obtained at lower concentrations (X0.3 mM) is probably due to inhibition of IGF-1R and Akt activity (Vasilcanu et al, 2004). The reduced protective effects of b-arrestin1 inhibition on cell viability at PPP doses of >1.25 mM could, on the other hand, be due to unspecific effects of the inhibitor.…”

“…Moreover, PPP reduced phosphorylation of Akt, induced caspase 3 activation and apoptosis and caused tumor regression in grafted mice Vasilcanu et al, 2004;Catrina et al, 2005;Ulfarsson et al, 2005;Conti et al, 2007;Menu et al, 2006;Stromberg et al, 2006;Tomizawa and Saisho, 2006;Vasilcanu et al, 2006;Colon et al, 2007;Razuvaev et al, 2007). PPP did, however, not affect growth of established R-vsrc (IGF-1RÀ/À) tumor grafts , suggesting selectivity for IGF-1R regarding tumor growth.…”

Dysregulation of growth factor signaling in human hepatocellular carcinoma

“…In the case of IGF-mediated signal transduction, highly specific RTK inhibitors are necessary to discriminate between IGF-1R and INSR (Pautsch et al, 2001) to prevent diabetogenic effects. Several highly selective inhibitors such as tyrphostins (Ohmichi et al, 1993;Parrizas et al, 1997;Blum et al, 2000Blum et al, , 2003, NVP-AEW541 (GarciaEcheverria et al, 2004;Scotlandi et al, 2005), NVP-ADW742 (Mitsiades et al, 2004;Warshamana-Greene et al, 2004 and cyclolignans Vasilcanu et al, 2004;Menu et al, 2005) reduce the activation of IGF-1R and downstream effectors such as AKT/PKB. In vitro as well as in vivo, these substances efficiently reduce tumor cell growth, often in combination with chemotherapeutic agents (Mitsiades et al, 2004;Scotlandi et al, 2005).…”

Role of insulin-like growth factor 1 receptor signalling in cancer

“…PPP did not compete with ATP but interfered with phosphorylation in the activation loop of the kinase domain, in which it specifically blocked phosphorylation of the tyrosine (Y) 1136 residue, while sparing the two others (Y1131 and Y1135). Since an IGF-1R construct, in which the tyrosine at position 1136 was replaced by a phenylalanine, also led to a strong inhibition of phosphorylated Akt in transfected cells, it was suggested that this mechanism may be responsible for the apoptotic effect of PPP (Vasilcanu et al, 2004). Unpublished studies have also demonstrated that the IGF-1Rs of PPP treated cells are undergoing rapid downregulation.…”