Growth hormone protects colorectal cancer cells from radiation by improving the ability of DNA damage repair

Abstract

The present study aimed to examine the effects of recombinant human growth hormone (rhGH) on the sensitivity of a colorectal cancer cell line to radiotherapy, and to investigate its association with DNA damage and repair. Flow cytometry and immunofluorescence were employed to detect growth hormone receptor (GHR) expression in nine human colorectal cancer cell lines. A colony forming assay was performed to measure the colorectal cancer cell proliferation post‑radiotherapy, as an indicator of radiotherapy sensitivity. The comet assay results were interpreted as an indicator of radiotherapy‑induced DNA damage, and growth arrest and DNA damage 45 (GADD45) and apurinic/apyrimidinic endonuclease (APEN) protein expression were quantified with western blot analysis from the same cell lines. The results demonstrated that the colony‑forming efficiency (CFE) was significantly increased in HCT‑8 cells subject to radiotherapy and rhGH pretreatment compared with the cells treated with radiotherapy alone, in a dose‑dependent manner (0‑100 mg/l). This effect was enhanced under high doses of radiation (8 Gy; 52.1±2.9 vs. 21.0±2.7; P<0.001) and was ameliorated with GHR neutralizing antibody exposure. By contrast, rhGH pre‑incubation did not change the colony formation rate in GHR(‑) LOVO cells. rhGH intervention reduced the early HCT‑8 cell DNA damage (21.53±2.88 vs. 36.56±3.93; P=0.003) as well as the following plateau phase, compared with cells treated with radiotherapy alone (5.5±0.42 vs. 9.07±0.84; P=0.012). rhGH upregulated GADD45 and APEN protein expression, which is associated with cellular stress responses and DNA damage repair (P=0.007). The results suggest that rhGH is able to protect colorectal cancer cells from radiation through the interaction with GHR, which is associated with the promotion of DNA damage repair activity.

MECHANISMS IN ENDOCRINOLOGY: Lessons from growth hormone receptor gene-disrupted mice: are there benefits of endocrine defects?

“…In an in vitro study, Lobie and colleagues had identified autocrine GH causing increased resistance of breast cancer cells (MCF7, T47D, and MDA-MB-231) to mitomycin-C (MMC)-induced apoptosis by protecting against DNA-damage(160). The identical protective effect of GH was also seen in HCT-8 colorectal cancer cells where recombinant human GH treatment protected the tumor cells against radiation in a dose-dependent manner (183). Mechanisms of chemotherapeutic resistance in cancer includes but are not limited to (i) abundant expression of a repertoire of drug efflux pumps (184,185,186,187), (ii) sequestration of drugs in melanosomes during melanogenesis (188,189), and (iii) upregulation of EMT markers (159,190,191,192,193,194), a critical mechanism of phenotype switch and chemotherapy evasion in several types of cancers(130, 131).…”

Growth Hormone Ameliorates the Radiotherapy-Induced Ovarian Follicular Loss in Rats: Impact on Oxidative Stress, Apoptosis and IGF-1/IGF-1R Axis

“…In agreement with these results, Madrid & coworkers [ 23 ] suggested that GH showed a dose- dependent protection against radiotherapy-induced cell death in CHO-4 cells due to DNA repairing mechanism. Wu and coworkers has recently reported that rhGH protects colorectal cancer cells from high dose irradiation by up-regulation of GADD45 and APEN protein expression, which is associated with cellular stress responses and DNA damage repair mechanisms [ 76 ]. Moreover, an in vitro data suggested that GH plays a role in follicular growth in the early gonadotropin-independent stage and could have a direct inhibitory action on follicle apoptosis [ 77 ].…”

The effects of growth hormone on therapy resistance in cancer

“…GH treated breast cancer cells MDA-MB-435S and T47D, as well as endometrial cancer cell RL95-2 showed markedly reduced DNA damage as well as heightened clonogenic survival post-irradiation [177] . GHR-expressing human colorectal cancer cells HCT-8, pretreated with different doses of recombinant hGH, showed a dosedependent increase in post-irradiation survival while comet assays exhibited reduced DNA damage [184] . The effects were again suppressed on exposure to an anti-GHR antibody [184] .…”

“…GHR-expressing human colorectal cancer cells HCT-8, pretreated with different doses of recombinant hGH, showed a dosedependent increase in post-irradiation survival while comet assays exhibited reduced DNA damage [184] . The effects were again suppressed on exposure to an anti-GHR antibody [184] . In animal studies, immunodeficient NIH-III mice with RL95-2 xenografts, when gamma irradiated with or without 100 mg/kg pegvisomant injections every alternate day, showed reduced growth and anti-vascular effects in animals subjected to GHR antagonism [185] .…”