Selective Disruption of Insulin-like Growth Factor-1 (IGF-1) Signaling via Phosphoinositide-dependent Kinase-1 Prevents the Protective Effect of IGF-1 on Human Cancer Cell Death

Abstract

The insulin-like growth factor (IGF)3 signaling system plays a key role in growth and development of many normal tissues and regulates overall growth of organisms (1). Type I insulin-like growth factor (IGF-1) has been identified as a regulator of cellular transformation and controls the acquisition of the tumorigenic phenotype by regulating multiple cellular functions that impact on the invasive/metastatic potential of cancer cells. These include cell survival, motility, invasion, growth potential in secondary organ sites, and the induction of angiogenesis (2). There are also several lines of evidence that dysregulation of the IGF-1 system is involved in resistance to certain anticancer therapies, including cytotoxic chemotherapy, hormonal agents, biological therapies, and radiation (3). The link between cancer and IGF signaling is also consistent with recent epidemiological studies showing an increased relative risk for the development of colon, prostate, breast, lung, and bladder cancers in individuals with circulating IGF-1 levels in the upper tertile of the normal range (4). These findings were confirmed in animal models, where reduced circulating IGF-1 levels result in significant reductions in cancer development, growth, and metastases, whereas increased circulating IGF-1 levels are associated with enhanced tumor growth (5).

PDK1 Recruitment to the SHPS-1 Signaling Complex Enhances Insulin-like Growth Factor-I-stimulated AKT Activation and Vascular Smooth Muscle Cell Survival

“…Prior studies have reported that IGF-I enhances PDK1 activity and increases cell survival (17,50). Our studies show that when SMCs are exposed to hyperglycemic stress, they undergo apoptosis unless they are exposed to IGF-I (42) and that assembly of the signaling complex on SHPS-1 is required to prevent apoptosis (26).…”

“…Growth factor stimulation leads to sequential phosphorylation of Tyr 9 and Tyr 373/376 (11,14,16,17), and substitutions for these phosphotyrosines result in decreased PDK1 activity (9,13,14,16,47). Previous studies showed that Pyk2 activates PDK1, but the mechanism was not determined (9,12,18).…”

“…PDK1 undergoes tyrosine phosphorylation in response to insulin, angiotensin II, high glucose, and insulin-like growth factor-I (IGF-I) 2 (9,(11)(12)(13)(14)(15)(16)(17). Previous studies indicate that optimal activation of PDK1 requires phosphorylation of Tyr 373/376 (11,12,14,17), and growth factor receptor activation leads to PDK1 recruitment to the plasma membrane, followed by sequential phosphorylation of Tyr 9 and then Tyr 373/376 (14,17). A previous study suggested that Pyk2 (proline-rich tyrosine kinase 2) plays an important role in PDK1 activation.…”

Insulin-like Growth Factor Receptor-1 and Nuclear Factor κB Are Crucial Survival Signals That Regulate Caspase-3-mediated Lens Epithelial Cell Differentiation Initiation

“…The importance of IGF-1R in cell survival has been well documented in the literature (26,47,49), and in the lens the expression of IGF-1R is up-regulated in the zone of differentiation initiation (or equatorial epithelium) (15,50). Although IGF-1 is known to be important in lens cell survival (16 -18, 51), the mechanism by which IGF-1R was required for signaling lens epithelial cell differentiation had previously remained unclear.…”

Neoplasms in Acromegaly

“…Доказано, что у человека инсулиноподобный ростовой фактор (ИРФ) 1-го типа играет опре-деленную роль в возникновении рака пред-стательной железы, молочной железы, толстой кишки, яичников, легкого, шейки матки [38].…”