Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor

Abstract

Cellular senescence suppresses cancer by arresting cell proliferation, essentially permanently, in response to oncogenic stimuli, including genotoxic stress. We modified the use of antibody arrays to provide a quantitative assessment of factors secreted by senescent cells. We show that human cells induced to senesce by genotoxic stress secrete myriad factors associated with inflammation and malignancy. This senescence-associated secretory phenotype (SASP) developed slowly over several days and only after DNA damage of sufficient magnitude to induce senescence. Remarkably similar SASPs developed in normal fibroblasts, normal epithelial cells, and epithelial tumor cells after genotoxic stress in culture, and in epithelial tumor cells in vivo after treatment of prostate cancer patients with DNA-damaging chemotherapy. In cultured premalignant epithelial cells, SASPs induced an epithelial–mesenchyme transition and invasiveness, hallmarks of malignancy, by a paracrine mechanism that depended largely on the SASP factors interleukin (IL)-6 and IL-8. Strikingly, two manipulations markedly amplified, and accelerated development of, the SASPs: oncogenic RAS expression, which causes genotoxic stress and senescence in normal cells, and functional loss of the p53 tumor suppressor protein. Both loss of p53 and gain of oncogenic RAS also exacerbated the promalignant paracrine activities of the SASPs. Our findings define a central feature of genotoxic stress-induced senescence. Moreover, they suggest a cell-nonautonomous mechanism by which p53 can restrain, and oncogenic RAS can promote, the development of age-related cancer by altering the tissue microenvironment.

Metformin‐mediated increase in DICER1 regulates microRNA expression and cellular senescence

“…A further hallmark trait of senescent cells is the secretion of inflammatory cytokines, chemokines, and oncogenes (the senescence‐associated secretory phenotype or SASP) (Coppe et al ., 2008). We quantified the levels of several mRNAs encoding SASP factors in WI‐38 cells, in IDH4 cells grown without dex, and WI‐38 and IMR‐90 cells exposed to IR.…”

Plasma proteomic signature of age in healthy humans

“…To determine enrichment of cell senescence proteins, a list of SASP proteins were compiled based on prior research (Coppe, Desprez, Krtolica, & Campisi, 2010; Coppe et al., 2008; Lasry & Ben‐Neriah, 2015). There were 72 unique SOMAmer Reagents that recognized proteins previously reported as SASP proteins.…”

Elimination of p19ARF‐expressing cells protects against pulmonary emphysema in mice

“…Senescence is executed by the activation of two major tumor suppressor pathways, the p19 ARF (p14 ARF in human)‐p53 and p16 INK4a ‐pRB pathways, which play critical roles in the induction and maintenance of cell cycle arrest during senescence (Ben‐Porath & Weinberg, 2005; Sherr, 2001). In addition to cell proliferation arrest, it is now evident that senescent cells secrete many pro‐inflammatory factors, proteinases, and other bioactive substances (Coppé et al, 2008). These substances are collectively called SASPs (senescence‐associated secretory phenotypes), through which senescent cells affect the functions of their surrounding nonsenescent cells.…”