Research Article: Induction, regulation and roles of neural adhesion molecule L1CAM in cellular senescence

Date Published: March 28, 2018

Publisher: Impact Journals

Author(s): Blanka Mrazkova, Rastislav Dzijak, Terezie Imrichova, Lenka Kyjacova, Peter Barath, Petr Dzubak, Dusan Holub, Marian Hajduch, Zuzana Nahacka, Ladislav Andera, Petr Holicek, Pavla Vasicova, Olena Sapega, Jiri Bartek, Zdenek Hodny.


Aging involves tissue accumulation of senescent cells (SC) whose elimination through senolytic approaches may evoke organismal rejuvenation. SC also contribute to aging-associated pathologies including cancer, hence it is imperative to better identify and target SC. Here, we aimed to identify new cell-surface proteins differentially expressed on human SC. Besides previously reported proteins enriched on SC, we identified 78 proteins enriched and 73 proteins underrepresented in replicatively senescent BJ fibroblasts, including L1CAM, whose expression is normally restricted to the neural system and kidneys. L1CAM was: 1) induced in premature forms of cellular senescence triggered chemically and by gamma-radiation, but not in Ras-induced senescence; 2) induced upon inhibition of cyclin-dependent kinases by p16INK4a; 3) induced by TGFbeta and suppressed by RAS/MAPK(Erk) signaling (the latter explaining the lack of L1CAM induction in RAS-induced senescence); and 4) induced upon downregulation of growth-associated gene ANT2, growth in low-glucose medium or inhibition of the mevalonate pathway. These data indicate that L1CAM is controlled by a number of cell growth- and metabolism-related pathways during SC development. Functionally, SC with enhanced surface L1CAM showed increased adhesion to extracellular matrix and migrated faster. Our results provide mechanistic insights into senescence of human cells, with implications for future senolytic strategies.

Partial Text

Human population is aging rapidly, raising serious global health and societal concerns, at the same time highlighting the urgent need to better understand the process of aging at the molecular, cellular and organismal levels. Recent research has revealed aging-associated accumulation in diverse tissues of the so-called senescent cells (SC) which, along with their secreted products, appear to causally contribute to aging [1,2]. From a broader perspective, the process of senescence is a cellular stress response leading to persistent activation of cell-cycle checkpoints and long-lasting cell-cycle arrest caused predominantly by lasting DNA damage signaling. SC play important pathophysiological roles in a number of processes during ontogenetic development of the mammalian organism [3]; for instance, senescence response takes part in wound healing [4] and tissue regeneration [5]. As a cellular fate commonly triggered by DNA damage response, cellular senescence is considered as a primary tumorigenesis barrier [6–8]. DNA damage-induced cellular senescence also accompanies genotoxic cancer therapies [9,10]. Long-lasting persistence of senescent cells in tissues can also induce various pathological changes affecting organismal homeostasis (see, e.g. references [1,2]). These effects are thought to be elicited by secretion from SC of a complex mixture of factors comprising components of the extracellular matrix, its modifiers such as proteases and their regulators, reactive oxygen species [11] and particularly cytokines including morphogens from the TGFβ family, pro-inflammatory species (e.g., IL1, IL6, IL8 [12];), and chemokines (such as MCP-1 [13];). The composition of the SC secretome (denoted as senescence-associated secretory phenotype; SASP) varies according to the cell type and mechanism of senescence induction [14]. Additional factors influencing the secretory response of SC, such as interactions of SC with surrounding cells and specific tissue microenvironment, likely exist at the organismal level. This complexity and variability of SASP is the reason why the effects of SASP on the tissue microenvironment and the pathogenic role of various types of SC remain poorly understood. Nevertheless, it was plausibly demonstrated that senescent cells can affect neighboring cells by induction of oxidative stress and DNA damage resulting in secondary (‘bystander’) senescence [11,15,16]. This ‘domino’ effect might contribute to the spread of a mild but chronic inflammatory environment especially in aging tissues [17]. It should also be noted that certain chemotherapeutic drugs are able to induce cellular senescence in normal tissues within the close proximity of tumors, which can also promote local inflammation and self-sustaining genotoxic environment.

Despite that cellular senescence is a phenomenon well characterized and recognizable in vitro and the detection of SC in tissues is now less problematic due to the recently published robust method for their detection [67], there is a lack of strictly specific markers that would unambiguously allow targeting of SC for therapeutic purposes [68]. In search of cell-surface determinants overrepresented on senescent cells, we identified adhesion molecule L1CAM as being enhanced on replicatively senescent BJ fibroblasts. Further analysis of L1CAM expression in different senescence-inducing scenarios revealed that L1CAM expression depends on cell type and senescence-inducing stimulus, it shows marked intra-population heterogeneity and multiple levels of control, including regulation of the cell surface exposure. Our data also show that the L1CAM signaling pathway is interlinked with Erk signaling in a reciprocal manner. Stimuli changing cellular metabolism such as glucose levels, inhibition of the mevalonate pathway, and suppression of ANT2 (SCL325A5) all affected the level of L1CAM expression, suggesting that L1CAM gene expression might be controlled by the metabolic changes accompanying the development of cellular senescence. The L1CAM level correlated with increased migratory properties of both proliferating and senescent BJ cells and with enhanced adhesion of cells to the components of extracellular matrix.




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