Abstract 5683: Growth hormone as a SASP component
Authors: Chesnokova Vera , Zonis Svetlana M. , Barrett Robert , Melmed Shlomo 
Published: June 2022

Senescence, largely initiated by unrepaired DNA damage, is initially sustained by upregulated p53. Although senescent cells enter proliferative arrest, early p53 supression may result in senescent cells re-entering the cell cycle. Senescent cells exhibit a senescence-associated secretory phenotype (SASP) that impacts the cell microenvironment, often promoting cell transformation. SASP molecular composition may be cell-specific and dependant on the type of SASP-producing cell. As growth hormone (GH) is induced by DNA damage, we elucidated whether GH is induced in senescent cells. Non-pituitary GH (npGH) synthesized locally in peripheral tissues is identical to endocrine GH1 produced by the pituitary and acts through autocrine/paracrine mechanisms via the widely expressed GH receptor that recognizes both pituitary GH and npGH ligands. We show that npGH is induced in aging human colon tissue, and in human non-tumorous colon cells and in human 3-dimensional intestinal organoids in response to oncogene-, therapy-, and/or replicative-induced senescence. Furthermore,DNA-damage-induced npGH is secreted from senescent cells, constituting a SASP component. In senescent cells, DNA damage is not repaired with fidelity, and we show that induced npGH suppresses DNA damage responses by attenuating phosphorylation of ATM, DNA-PKc, p53 and Chk2, resulting in p53 suppression and accumulation of damged DNA. Autocrine npGH also triggers senescent cell proliferation with increased Ki67 and BrdU incorporation. As proliferating cells with accumulated unrepaired DNA damage may acquire oncogenic mutations,we assessed npGH actions on cell transformation. We show that senescent colon cells expressing npGH form colonies in soft agar,while GH depletion by shRNA downregulates Ki67 and decreases colony formation and size, suggesting that npGH enables senescent cell transformation. Consistent with a SASP function, induced paracrine npGH also suppresses the p53/p21 pathway, triggering proliferation and exacerbates DNA damage in neighboring non-senescent cells. To further explore mechanisms underlying npGH induction we tested the role of the SASP chemokine CXCL1 which attracts immune effectors to eliminate senescent cells. CXCl1 is shown to induce npGH in senescent hNCC and in intestinal organoids, while GH, in turn, suppresses CXCL1, likely by inhibiting NFκB, a CXCL1 transcription factor. Both colon CXCL1 and NFκB are more abundant in GH-receptor knockout mice devoid of GH signalling, while mice bearing GH-secreting xenografts exhibit decreased colon CXCL1 abundance. Conclusions: The results elucidate a heretofore unappreciated GH action, whereby npGH, as a SASP component, attenuates senescent cell elimination by inhibiting CXCL1, and contributes to a tissue microenvironment favoring age-associated DNA damage accumulation and epithelial cell transformation.

Citation Format: Vera Chesnokova, Svetlana M. Zonis, Robert Barrett, Shlomo Melmed. Growth hormone as a SASP component [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5683.