Hallmarks for senescence in carcinogenesis: novel signaling players

Abstract

Cellular senescence is a potent anti-cancer mechanism controlled by tumor suppressor genes, particularly p53 and pRb, which is characterized by the irreversible loss of proliferation. Senescence induced by DNA damage, oncogenic stimulation, or excessive mitogenic input, serves as a barrier that counteracts cancer progression. Emerging evidence in cellular and in in vivo models revealed the involvement of additional signaling players in senescence, including PML, CK2, Bcl-2, PI3K effectors such as Rheb, Rho small GTPases, and cytokines. Recent studies have also implicated protein kinase C (PKC) isozymes as modulators of senescence phenotypes and showed that phorbol esters, widely used PKC activators, can induce senescence in a number of cancer cells. These novel findings suggest a complex array of cross-talks between senescence pathways and may have significant implications in cancer therapy.

The Intricate Interplay between Mechanisms Underlying Aging and Cancer

“…The cell cycle arrest and the ensuing downstream events of the cellular senescence program are orchestrated by complex circuits integrating several signaling pathways and networks, including: (1) the p14ARF/p53 and p16INK4a/pRB tumor suppressor pathways, two master regulator pathways of senescence that are activated by various cell-intrinsic and cell-extrinsic stresses in a parallel-(in human fibroblasts) or linear (in mouse fibroblasts) fashion; (2) the Ras/Raf/MEK/ERK/mTOR oncogene signaling pathway; (3) the PI3K/PTEN/Akt/mTOR nutrient-sensing signaling pathway; (4) the Wnt/HIRA/ASF1a/UBN1 chromatin remodeling pathway; and (5) the C/EBPβ-and NFκB-governed senescence secretome transcriptional network [3, 4, 5, 12-14, 22, 33, 44, 45, 86, 117-138]. These signaling pathways: (1) transmit signals generated by sensor and effector proteins in response to individual senescence triggers (cell-intrinsic or cell-extrinsic) or to their combinations; (2) are linked via a series of connections; (3) are integrated into circuits by the p14ARF/p53 and p16INK4a/pRB master regulator pathways of senescence; (4) govern the spatiotemporal organization of the multistep cellular senescence program; and (5) elicit various hallmark features of the senescent phenotype [3,5,12,13,22,44,86,124]. A detailed description of the signaling circuitry characteristic of the cellular senescence program is beyond the scope of this review; the recent significant progress in this area has been comprehensively summarized elsewhere [3,5,12,22,44,86,124].…”

“…These signaling pathways: (1) transmit signals generated by sensor and effector proteins in response to individual senescence triggers (cell-intrinsic or cell-extrinsic) or to their combinations; (2) are linked via a series of connections; (3) are integrated into circuits by the p14ARF/p53 and p16INK4a/pRB master regulator pathways of senescence; (4) govern the spatiotemporal organization of the multistep cellular senescence program; and (5) elicit various hallmark features of the senescent phenotype [3,5,12,13,22,44,86,124]. A detailed description of the signaling circuitry characteristic of the cellular senescence program is beyond the scope of this review; the recent significant progress in this area has been comprehensively summarized elsewhere [3,5,12,22,44,86,124].…”

“…By establishing a positive feedback loop to sustain ROS/PKC-δ signaling, PKC-δ irreversibly blocks cytokinesis (Figure 1) [14,124,[178][179][180]. Noteworthy, some genetic manipulations and senescence triggers in culture can cause a senescenceassociated irreversible S, G2 or G2/M cell cycle arrest [12,101,[181][182][183].…”

“…The p16INK4a/pRB tumor suppressor pathway also responds to various senescence triggers by modulating Rac1 and Cdc25. These two members of the Rho family of small GTPases then alter cytoskeleton dynamics and a pattern of gene transcription to orchestrate senescenceassociated changes in cell size, shape, morphology, motility and adhesion (Figure 1) [124,[184][185][186][187][188][189][190]. Moreover, a significant enlargement of cells entering a state of senescence is caused by the AMPK/TOR signaling pathway, which promotes ribosome biogenesisand protein translation in the cytosol under the conditions of a senescence-associated irreversible cell cycle arrest (Figure 1) [9,24,80,140,[191][192][193][194][195].…”

“…Cells that entered a state of senescence in culture are resistant to apoptotic death elicited by certain proapoptotic stimuli [12,124,[196][197][198][199][200][201][202]. The resistance of these cells to apoptosis is due in part to elevated expression of a gene encoding the anti-apoptotic Bcl-2 protein [124,198,[203][204][205][206][207].…”