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Stress-Induced Cellular Senescence Contributes to Chronic Inflammation and Cancer Progression

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Stress-Induced Cellular Senescence Contributes to Chronic Inflammation and Cancer Progression Current knowledge of molecular and cellular biology of cellular senescence・ S. Kobashigawa et al. Review Thermal Med, 35 (4): 41-58, 2019. Stress-induced Cellular Senescence Contributes to Chronic Inflammation and Cancer Progression SHINKO KOBASHIGAWA1,2, YOSHIHIKO M. SAKAGUCHI1, SHINICHIRO MASUNAGA2, EIICHIRO MORI1* 1Department of Future Basic Medicine, Nara Medical University, Kashihara, Nara, 634-8521, Japan 2Kyoto University, Institute of Integrated Radiation and Nuclear Science, Kumatori, Osaka, 590-0494, Japan Abstract: Cellular senescence has long been considered to act as a tumor suppressor or tumor suppression mechanism and described as a phenomenon of irreversible cell cycle arrest. Cellular senescence, however, is now considered to have physiological functions other than tumor suppression; it has been found to be involved in embryogenesis, tissue/organ aging, and wound healing. Surprisingly, cellular senescence is also demonstrated to have a tumor progressive role in certain situations. Senescent cells exhibit secretory phenotypes called senescence-associated secretory phenotype (SASP), which secrete a variety of SASP factors including inflammatory cytokines, chemokines, and growth factors, as well as matrix remodeling factors that promote the alteration of neighboring tissue microenvironments. Such SASP factors have been known to drive the mechanisms underlying the pleiotropic features of cellular senescence. In this review, we examine current knowledge of cellular senescence at molecular and cellular levels, with a focus on chronic inflammation and tumor progression. Key Words: senescence, senescence-associated secretory phenotype (SASP), reactive oxygen species (ROS), ionizing radiation, heat shock response (HSR) 1. Introduction Hayflick and Moorhead1) were the first to describe the limited divisions of cells and term this irreversible cell cycle arrest as cellular senescence. Senescent cells remain metabolically active, but their growth is irreversibly halted and their morphological characteristics altered as large, flat, and refractile2,3). Irreversible cell cycle arrest is now thought to be dependent upon the shortening of telomeres; an expression of the catalytic subunit of the telomerase holo-enzyme (hTERT) is enough to bypass cellular senescence4-6). Telomeres are folded d-loop/t-loop structures located at the ends of chromosomes that serve to mask DNA ends from being recognized as DNA double-strand-breaks (DSBs)7,8). Telomerase activity is absent from most normal human somatic cells. After serial divisions, telomeres become too short to have sufficient binding sites for shelterin proteins (the latter being protein complexes known to protect telomeres) and are remodeled with a “capped” structure9). Telomere shortening-related senescence is called replicative senescence. Nonetheless, mouse Received 5 June, 2019, Accepted 28 Oct, 2019: *Corresponding author; Tel, +81-744-25-7657; e-mail, [email protected] doi: 10.3191/thermalmed.35.41 ©2019 Japanese Society for Thermal Medicine ― ―41 Thermal Med, 35[4]: 41-58, 2019. embryonic fibroblasts (MEFs) undergo cellular senescence despite telomerase activity5). Senescence in vitro can be bypassed by culturing in serum-free media or low oxygen conditions in MEFs5,10,11). Cellular senescence is hence, induced not only by telomere shortening, but also by certain culture conditions5). Several studies found that irreversible cell cycle arrest can be induced when normal cells are exposed to a variety of stressors, including telomere erosion, oxidative stress, ionizing radiation, and the activation of oncogenes such as Ras12-17). Such cellular senescence is called premature senescence, and is also known as stress-induced senescence (SIS) or oncogene-induced senescence (OIS). Senescence induced by oncogenic stimuli is recognized as a tumor suppression mechanism due to its irreversible arrest of proliferation18,19). However, findings from recent studies suggest that the secretion of inflammatory cytokines, chemokines, and the induction of matrix remodeling factors in senescent cells lead to inflammation and cancer progression5,20). This phenomenon is known as senescence-associated secretory phenotype (SASP) and as summarized in Tables I and II, SASP factors are associated with multiple functions, either in the suppression or progression of tumorigenesis. The role of this process is dependent on p53-induced cellular senescence; p53 null/mutant cells bypass senescence, and accelerates tumor growth and invasiveness after SASP factor Table I. A summary of the functions and mechanisms of SASP factors and multiple roles of cellular senescence in vivo mouse study. Senescent cells are shown to have multiple functions (e.g. embryogenesis, aging, wound healing, tumor suppression, tumor promotion) in vivo. Function Activation stimuli SASP factors Possible mechanism ── TGFβ/SMAD and PI3K/FOXO-p21-senescence-tissue ── / remodeling (ref. 22) Embryogenesis Development TGFβ SMAD, CEBPβ, CSF1 ── p21, p15- senescence- SASP- tissue growth patterning (ref. 23) ぉぐけぐく BubR1H/H ── (‒) ── p16- senescence- age related dysfunction (ref. 29) Naturally-occurring (RS?) ── (‒) ── p16- senescence- age related dysfunction (ref. 30) Aging senescence RS ── IFNα, IL6, TNFα, MX1 ── telomere instability-cytosolic DNA- cGAS/STING- SASP- HP1β and p16- senescence (ref. 114) ぉ ぐこけこぐ く ぉこけこく CCl4 ── IL11, IL8, IL6 ── CCl4-p53/16 dependent senescence-SASP- immune system- reduced liver fibrosis (ref. 31) Wound healing Bacterial artificial ── PDGF-AA ── injury-senescent fibroblasts and endothelial cells- SASP- wound healing (ref. 32) chromosome (BAC), IR (X-ray) Δgut CKIα knockout ── IκB, TNF, factors ── CKIαΔgut-DNA damage response-SASP factor-p53 Tumor suppressed by NSAID dependent senescence (ref. 21) suppression Ras ── TGFβ family ligands, ── Ras-IL1 signaling-TGFβ family, VEGF, CCL2 and VEGF, CCL2, CCL20 CCL20-p15 and p21-senescence (ref. 101) Δgut ぉぐけぐく CKIα knockout ── IκB, TNF, Factors ── CKIαΔgut-DNA damage response-SASP (p53 mutation/ suppressed by NSAID null) proinvasive gene expression signature (ref. 21) Tumor Obesity or DMBA ── IL6, Groα, CXCL9 ── obesity-deoxycholic acid-DNA damage-SASP factors promotion -promote hepatocellular carcinoma (ref. 94) Bleomycin, RS ── IL6, IL8, GM-CSF ── p38-AUF1-SASP factors-tumor promotion (ref. 119) Inflammation RS, H-RasV12E-, etoposide ── IL1α, IL8 ── cytoplasmic chromatin-cGAS/STING-NFκB-SASP (ref. 110) Drug resistance doxorubicin ── IL6, Timp1 ── doxysolbicin-p38 activation-IL6 from the thymic stroma- lymphoma cell surviving (ref. 109) ― ―42 Current knowledge of molecular and cellular biology of cellular senescence・ S. Kobashigawa et al. signaling21). It remains unclear why cells become senescent, yet are not removed from the tissue. This suggests that cellular senescence may have a role other than the suppression of tumorigenesis. Muñoz-Espín et al.22) and Storer et al.23) proposed that the cells become senescent as part of embryogenesis fine-tuning. Both studies found that senescent cells contribute to macrophage infiltration and tissue formation through SASP22,23). Cellular senescence is associated with a number of other functions, including organismal aging (Table I). The accumulation of senescent cells is typically observed in aging tissues24-28). Studies have found that the removal of senescent cells from the tissue prolongs mice lifespan and prevents age-dependent changes in several organs29,30). Yet, cellular senescence has also been shown to limit the extent of fibrosis following liver damage, and underscore the interplay between senescent cells and the tissue microenvironment31). This finding demonstrates the contribution of cellular senescence in an additional role of wound-healing and repair in tissue31,32). Due to its multiple roles, researchers argue that there may be different types of cellular senescence (Tables I and II). For example, the expression of telomerase has been found to prevent cellular senescence, but not epigenetic aging or DNA methylation-based aging; Kabacik and colleagues33) suggest that each senescent cell and paracrine cell may have different epigenetic aging backgrounds. In another study, senescent cells during development are removed by immune system such as macrophage and thought not to be associated with DNA damage response22,34). Table II. A summary of the functions and mechanisms of SASP factors and multiple roles of cellular senescence in vitro study. SASP factors are shown to have multiple functions including the establishment of cellular senescence in vitro. Function SASP factors Possible mechanismmj ぉ ぐ ぐ ぐ ぐこけぐこぐぐ ぐIL く 6, IL8, IL1α, IL1α ―― Ras-ROS-DNA damage-decrement of histone methylation-SASP factors (ref. 12) Factors bind to CXCR2 ―― NFκB and C/EBPβ-chemokines-CXCR2 (IL8RB)-p53 dependent senescence (ref. 13) PAI-1 ―― p53- PAI1-PKB↓- GSK3β-cytosolic CyclinD1-senescence (ref. 53) IGFBP7 ―― BRAFV600E-MEK-ERK-IGFBP7-down reguration of MEK and ERK (ref. 54) Senescence IGFBP5 ―― IGFBP5-p53-senescence (ref. 55) IL1, IL6, TGFβ ―― TGFβ and IL1 signaling pathways-Nox4-ROS-DNA damage-paracrine senescence (ref. 104) IL6, TNFα, factors related cGAS ―― ROS-chromatin framents in cytosol-cGAS-SASP factors (ref. 111) Factors related cGAS/STING ―― telomere instability-cytosolic DNA-cGAS/STING-autophage-senescence (ref. 113) ぉぐぐけぐぐく IL6, IL8, IL1β, GROα, GM-CSF, ―― senescence-SASP factors (ref. 50) IGFBP2 IL1α, IL6, NFκB, CXCL1, CXCL2 ―― mTOR-SASP factors-prostate tumour growth (ref. 102) Tumor promotion IL1α, IL6, NFκB, IL8
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