Excess growth hormone suppresses DNA damage repair in epithelial cells

The effects of growth hormone on therapy resistance in cancer

“…The studies which used a post-irradiation GH treatment to effect recovery of non-tumor cells, did not include a long-term follow up on any subsequent neoplasmic occurrences in the same patients. This could be pivotal based on the above-mentioned recent reports by Chesnokova et al [97] , where a GH excess although anti-apoptotic, actually inhibits DDR, thereby allowing oncogenic transformation in epithelial cells [97] .…”

“…As early as 2004, GH overexpressing EL4 T-cell lymphomas were reported to have reduced apoptosis when treated with methyl methanosulfonate (MMS) and reduced levels of Bax, BAD, and caspases-3, 8, and 9 [95] . A series of reports, especially from Melmed and colleagues, described a GH-induced feedback inhibition on p53 following DNA-damage in cells [96][97][98] . They showed that Nutlin-induced DNA damage and induction of the p53/p21 senescent pathway lead to GH expression in vitro in rodent primary pituitary cultures, in human pituitary adenoma samples and in vivo in C57BL/6 mice [98] .…”

“…Tip60 mediated suppression of ATM (Ataxia-Telangiesctasia mutated) activation [97] . ATM is induced by DNA-damage and p53 is a primary ATM-target [93,101] .…”

“…ATM is induced by DNA-damage and p53 is a primary ATM-target [93,101] . A recent study revealed increased DNA damage repair (DDR) in GHRKO mice colon and human non-tumor colon cells (hNCC); whereas etoposide and 500ng/mL GH led to increased transformation of hNCC and increased metastasis in colon tumor xenograft bearing mice [97] . Thus locally produced GH, in response to therapy induced DNA damage, clearly foster a "milieu permissive of neoplastic growth" [96] by rescuing cells from committing to senescence [98] , protecting them from apoptosis [96] , or allowing oncogenic mutations by blocking DDR [97] , wherein p53 is a central target of GH-induced oncogenicity and therapy evasion.…”

“…A recent study revealed increased DNA damage repair (DDR) in GHRKO mice colon and human non-tumor colon cells (hNCC); whereas etoposide and 500ng/mL GH led to increased transformation of hNCC and increased metastasis in colon tumor xenograft bearing mice [97] . Thus locally produced GH, in response to therapy induced DNA damage, clearly foster a "milieu permissive of neoplastic growth" [96] by rescuing cells from committing to senescence [98] , protecting them from apoptosis [96] , or allowing oncogenic mutations by blocking DDR [97] , wherein p53 is a central target of GH-induced oncogenicity and therapy evasion. Podlutsky et al [102] have shown improved DDR capacities and upregulated p53-target genes like Gadd45b and Mdm2 in primary fibroblasts from GH/IGF1 deficient Lewis dwarf rats and dwarf Snell mice [102] , further bolster the argument presented here that GH action attenuates p53 action and can be a critical oncogenic factor.…”