Endocrine Abstracts (2017) 49 S23.2 | DOI: 10.1530/endoabs.49.S23.2

Is GH a cancer growth factor?

Shlomo Melmed


USA.


Acromegaly is associated with increased soft tissue neoplasms, while GH deficient patients are protected from cancer development. Both environmental and age-related signals lead to cellular senescence and cell cycle dysregulation. We have shown that DNA damage-induced cellular senescence increases GH by inducing p53. GH, in turn, suppresses tumor suppressor proteins in both pituitary and nonpituitary cells.These observations led us to propose that intracellular epithelial GH in the mucosal microenvironment may enable neoplastic growth. Mechanisms underlying pro-neoplastic GH actions include: knockdown or suppressing either GH or GHR mRNA induces p53; GH suppresses p53 by inhibiting PTEN,a p53 acetylator, which protects p53 from ubiquitination, and up-regulates TRIM29, which also destabilizes p53. Thus, p53 ubiquitination and altered acetylation underlie suppression of p53 mediated by GH. GH also induces mTOR, EMT transcription factors and enhanced cell motility. In vivo epithelial p53 is markedly induced in GH-deficient Prop1−/−, and in GH receptor deficient GHR−/− mice, and in mutant GH receptor (Laron syndrome) fibroblasts. In nutlin-treated mice with DNA damage, GH is induced in colon epithelial cells. Doubly mutant Prop1−/− (GH-deficient) and Apcmin+/− (develop intestinal tumors) mice exhibit high colon p53 and markedly decreased intestinal tumor number and size compared to single mutant APC min+/− mice.GHR blockade induced by pegvisomant treatment of acromegaly patients leads to increased colon mucosal p53 and its transcriptional target p21. Overexpressing intracellular GH, or re-introducing WT GHR to mutant human fibroblasts, suppresses p53 thereby evading cellular senescence.

Conclusions: We hypothesize that GH leads to a pro-neoplastic environment and that high intracellular GH is a component of the field change enabling colon mucosal proliferation. GH-mediated senescence evasion may explain why GH deficiency is protective for cancer.

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