Role of IGF-1 receptor in radiation response

Abstract

Insulin-like growth factor 1 receptor (IGF-1R) is a transmembrane receptor tyrosine kinase involved in the development and progression of cancer whose activation strongly promotes cell growth and survival. IGF-1R exerts its main actions through the activation of the mitogen-activated protein kinase and phosphoinositide 3-kinase pathways. In addition to their traditional roles, IGF-1R activation has been associated with increased radioresistance both in vitro and in vivo, although the molecular mechanisms behind this process are still unclear. Recently, IGF-1R has been associated to new partners as major vault proteins, BCL-2, BAX, or Ku70/80, related to radiochemotherapy resistance, regulation of apoptosis, and nonhomologous end-joining DNA repair. Here, we review these novel associations of IGF-1R trying to explain the resistance to radiotherapy mediated by IGF-1R. Finally, we revised the role of new therapies leading to block the receptor to enhance the efficacy of radiation.

Figure 1

Signaling pathways of IGF-1R and its related functions in the cell. The figure shows the IGF-1R receptor, its main substrates, and the signaling pathways triggered as a consequence of its activation. Different colors encompass molecules implicated in the different cellular functions: blue, promotion of cell survival and antiapoptotic effect; orange, cell motility and invasion; and pink, cell proliferation and mitogenic activity. Arrows represent activation. Note that this diagram is a simplification and some effectors could be missing.

Figure 2

IGF-1R and its clinical relation to molecules involved in cell proliferation, apoptosis, and DNA repair. (→) represents positive correlation, whereas (⊣) represents negative correlation [51,52].

Figure 3

Main signaling pathways triggering by IGF-1R leading to RT resistance.