Growth hormone is a cellular senescence target in pituitary and nonpituitary cells

Abstract

Premature proliferative arrest in benign or early-stage tumors induced by oncoproteins, chromosomal instability, or DNA damage is associated with p53/p21 activation, culminating in either senescence or apoptosis, depending on cell context. Growth hormone (GH) elicits direct peripheral metabolic actions as well as growth effects mediated by insulin-like growth factor 1 (IGF1). Locally produced peripheral tissue GH, in contrast to circulating pituitary-derived endocrine GH, has been proposed to be both proapoptotic and prooncogenic. Pituitary adenomas expressing and secreting GH are invariably benign and exhibit DNA damage and a senescent phenotype. We therefore tested effects of nutlininduced p53-mediated senescence in rat and human pituitary cells. We show that DNA damage senescence induced by nutlin triggers the p53/p21 senescent pathway, with subsequent marked induction of intracellular pituitary GH in vitro. In contrast, GH is not induced in cells devoid of p53. Furthermore we show that p53 binds specific GH promoter motifs and enhances GH transcription and secretion in senescent pituitary adenoma cells and also in nonpituitary (human breast and colon) cells. In vivo, treatment with nutlin results in up-regulation of both p53 and GH in the pituitary gland, as well as increased GH expression in nonpituitary tissues (lung and liver). Intracrine GH acts in pituitary cells as an apoptosis switch for p53-mediated senescence, likely protecting the pituitary adenoma from progression to malignancy. Unlike in the pituitary, in nonpituitary cells GH exerts antiapoptotic properties. Thus, the results show that GH is a direct p53 transcriptional target and fulfills criteria as a p53 target gene. Induced GH is a readily measurable cell marker for p53-mediated cellular senescence.pituitary hormone | acromegaly

Growth hormone is permissive for neoplastic colon growth

“…High circulating GH levels can be caused by a GH-secreting pituitary tumor, and local colon GH can be induced as a result of DNA damage (51) or inflammation as within the pituitary gland (94). Regardless of the origin, high GH appears to exhibit properties of a component of the field change milieu affecting normal colon cells.…”

“…Immunoprecipitation and real-time PCR, SA-β-galactosidase Activity, cell proliferation assay and motility assay were performed as previously described (51,95). For details, see SI Methods.…”

“…We previously detected immunoreactive GH in both cell lines (51). Nontransformed hNCC were stably infected with lentivirus expressing human shGH RNA, whereas HCT116 cells were transfected with siGH RNAi.…”

Evidence of cellular senescence during the development of estrogen-induced pituitary tumors

“…Previous studies have already reported that murine pituitary adenomas with altered PTTG and Rb expression trigger cellular senescence (Chesnokova et al 2007(Chesnokova et al , 2008. These authors also correlated the high levels of growth hormone (GH) with the senescence-associated markers in adenomas, and suggested that cellular senescence is activated in a lineage-specific fashion ( Chesnokova et al 2008Chesnokova et al , 2011Chesnokova et al , 2013. However, to date, no attempt has been made to analyze the emergence of cellular senescence with pituitary tumor progression in the absence of genetic manipulation or specific senescence-inducing stimuli.…”

“…pituitary senescence being a cytological stress response (Marcotte et al 2004). In this way, senescence might be a more appropriate mechanism for pituitary tumor suppression, taking into account that the pituitary gland is critical for the homeostatic function, but which exhibits a regenerative capacity (Chesnokova et al 2013).…”