Dual Characters of GH-IGF1 Signaling Pathways in Radiotherapy and Post-radiotherapy Repair of Cancers

Abstract

Radiotherapy remains one of the most important cancer treatment modalities. In the course of radiotherapy for tumor treatment, the incidental irradiation of adjacent tissues could not be completely avoided. DNA damage is one of the main factors of cell death caused by ionizing radiation, including single-strand (SSBs) and double-strand breaks (DSBs). The growth hormone-Insulin-like growth factor 1 (GH-IGF1) axis plays numerous roles in various systems by promoting cell proliferation and inhibiting apoptosis, supporting its effects in inducing the development of multiple cancers. Meanwhile, the GH-IGF1 signaling involved in DNA damage response (DDR) and DNA damage repair determines the radio-resistance of cancer cells subjected to radiotherapy and repair of adjacent tissues damaged by radiotherapy. In the present review, we firstly summarized the studies on GH-IGF1 signaling in the development of cancers. Then we discussed the adverse effect of GH-IGF1 signaling in radiotherapy to cancer cells and the favorable impact of GH-IGF1 signaling on radiation damage repair to adjacent tissues after irradiation. This review further summarized recent advances on research into the molecular mechanism of GH-IGF1 signaling pathway in these effects, expecting to specify the dual characters of GH-IGF1 signaling pathways in radiotherapy and post-radiotherapy repair of cancers, subsequently providing theoretical basis of their roles in increasing radiation sensitivity during cancer radiotherapy and repairing damage after radiotherapy.

Keywords: DNA damage repair; GH-IGF1 signaling pathway; cancers; radio-resistance; radiotherapy.

FIGURE 1

Structure and function of somatotrophic system. Somatotrophic system begins with hypothalamus, through the pituitary to the liver, ends in the target organs, impacting numerous physiological systems, such as nervous system, skeletal system, muscular system, reproductive system, and immune system, with wide-ranging effects. It involves circulating GH and IGF1, and the local production of GH and IGF1, which are the main determinant of postnatal body growth.

FIGURE 2

Mechanism of GH in promoting cancer progression by binding to GHR. GH activates multiple signaling pathways by binding to its receptor GHR to promote the development of various cancers through the inducing of cell proliferation, invasion, migration and inhibiting cell apoptosis.

FIGURE 3

Intracellular mechanism of IGF-1 in promoting cancer progression by binding to IGF-1R. IGF-1 activates PI3K/Akt and Ras/MAPK/ERK1/2 signaling pathways by binding to its receptor IGF-1R to promote the development of various cancers through the inducing of cell survival, cell metabolism, invasion, migration and inhibiting cell apoptosis and autophagy.

FIGURE 4

Mechanism of GH-IGF-1 signaling in resistance to radiotherapy. (A) GH regulates radio-resistance by inducing HR pathway to repair DNA damage and decreasing pro-apoptotic molecules. (B) IGF-1 regulates radio-resistance by promoting cell proliferation, inducing NHEJ pathway to repair DNA damage and attenuating cell apoptosis.

FIGURE 5

Mechanism of IGF-1 signaling in promoting DNA damage repair. Signaling pathways mediated by IGF-1/IGF-1R promotes DNA repair by NHEJ through increasing phosphorylated DNA-PKcs and Ku70/Ku80 expressions and by HR through inducing phosphorylated ATM, γH2AX, p53BP-1, and PARP-1 expression levels.