CommentaryAccelerated senescence: An emerging role in tumor cell response to chemotherapy and radiation
Section snippets
Features of replicative senescence
It has long been appreciated that somatic cells have a finite proliferative capacity, termed the “Hayflick Limit”[1] and that this mortal state is controlled by an “internal clock”[2]. When cultured cells reach their proliferative limit, they adopt an enlarged and flattened morphology, increased granularity, and a vacuole-rich cytoplasm, while remaining viable and metabolically active. This permanent growth arrested state is referred to as replicative senescence. Besides these classic
Signaling elements that regulate replicative senescence
The one gene that is perhaps most strikingly implicated in replicative senescence is p53 [22]. In vitro data indicate that p53 binds to single-strand overhangs and cooperates with TRF2 in the formation of t-loop structures [23], suggesting a possible role for p53 in recognizing deprotected telomeres as damaged DNA. The replicative senescence resulting from telomere erosion is associated with enhanced phosphorylation of p53 at serines 15, 18 and 376 and reduced phosphorylation at serine 392 [24]
The accelerated senescence response to chemotherapy and radiotherapy
Accelerated senescence is characterized by the rapid induction of a permanent growth arrested state with many of the same morphological and biochemical features described above for replicative senescence. One notable exception is that accelerated senescence of cancer cells is not p16-dependent, as this cyclin dependent kinase inhibitor is silenced in the majority of cancer cell lines that readily undergo senescence in response to DNA damage [42]. While a variety of cellular stresses have been
Telomeres and telomerase in accelerated senescence
Since cancer cells typically have relatively short telomeres [77], and telomere attrition contributes to induction of replicative senescence [6], [7], it is logical to assume that cancer cells senescing in response to chemotherapy and/or ionizing radiation involved a telomere-length-dependent process. Through ectopic expression of hTERT as a means to elongate telomeres, it proved feasible to directly test the telomere length dependency on the kinetics and frequency of induction of accelerated
Are replicative and accelerated senescence separate pathways?
The early discoveries that replicative senescence is dependent on the activity of the tumor suppressor p53, the cyclin dependent kinase inhibitory protein p21waf1/cip1 and dephosphorylation of pRb, hinted that senescence is highly reminiscent of the DNA damage response pathway leading to G1 arrest (Fig. 2). This is in fact intuitive since exposed ends of linear chromosomes would be sensed as double strand breaks. As discussed above, the list of telomere-associated proteins has grown, with many
Accelerated senescence as a barrier to tumor growth and disease recurrence
Numerous studies have relied exclusively on the in vitro response of cancer cells to chemotherapeutic agents and irradiation, raising the question of whether senescence might merely be a tissue culture artifact. One limitation to assaying senescence in vivo is the paucity of senescence-associated markers. While the identification of senescence in cells is often based on the distinct cellular morphology together with senescence-associated β-galactosidase (SA-β-gal) activity at pH 6.0 [3], this
Accelerated senescence: a dead-end or detour?
Historically, senescence has been defined as a permanent growth arrested state, despite the fact that technical difficulties remain in the discrimination of a truly irreversible condition and a reversible long-term growth arrested state. In vitro data indicating that senescent cells can re-enter the cell cycle [21], [56], [59], [67] casts some doubt on this “permanent” growth arrested state. This proliferative recovery has been achieved, however, by selectively inactivating critical mediators
Concluding remarks
Overall, it has become evident that accelerated senescence must be considered a critical component of the tumor cell response to various modes of stress imposed by chemotherapeutic drugs and radiation. Furthermore, senescence appears to be sufficient to promote tumor regression, at least in experimental animal model systems. Accelerated senescence clearly plays a role in the drug and radiation treatment response in patients, although the relative contributions of the different modes of cell
Acknowledgements
Support of research in the laboratories of Gewirtz, Holt and Elmore has been provided by the NIH, Department of Defense and American Institute for Cancer Research. We are grateful to Ms. Sarah Schoch for assistance with the reference section. We regret that we were unable to cite all relevant studies in the literature. Due to the fact that, in several circumstances, no appropriate reviews were available, it was necessary to select one or two primary papers for citation while other equally
References (109)
- et al.
The serial cultivation of human diploid cell strains
Exp Cell Res
(1961) - et al.
Role of telomeres and telomerase in genomic instability, senescence and cancer
Lab Invest
(2007) - et al.
Mammalian telomeres end in a large duplex loop
Cell
(1999) - et al.
Telomere dysfunction in genome instability syndromes
Mutat Res
(2004) - et al.
P53 binds telomeric single strand overhangs and T-loop junctions in vitro
J Biol Chem
(2002) - et al.
Pathways governing G1/S transition and their response to DNA damage
FEBS Lett
(2001) - et al.
Mutant p53 can delay growth arrest and loss of CDK2 activity in senescing human fibroblasts without reducing p21(WAF1) expression
Exp Cell Res
(2003) - et al.
Senescence delay of human diploid fibroblast induced by anti-sense p16INK4a expression
J Biol Chem
(2001) - et al.
The ATM/p53/p21 pathway influences cell fate decision between apoptosis and senescence in reoxygenated hematopoietic progenitor cells
J Biol Chem
(2005) - et al.
Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a)
Mol Cell
(2004)
The signals and pathways activating cellular senescence
Int J Biochem Cell Biol
Irreversible cellular senescence induced by prolonged exposure to H2O2 involves DNA-damage-and-repair genes and telomere shortening
Int J Biochem Cell Biol
Expression of human telomerase (hTERT) does not prevent stress-induced senescence in normal human fibroblasts but protects the cells from stress-induced apoptosis and necrosis
J Biol Chem
Transforming growth factor beta triggers two independent-senescence programs in cancer cells
Biochem Biophys Res Commun
Oncogene-induced senescence pathways weave an intricate tapestry
Cell
Adriamycin-induced senescence in breast tumor cells involves functional p53 and telomere dysfunction
J Biol Chem
If not apoptosis, then what? Treatment-induced senescence and mitotic catastrophe in tumor cells
Drug Resist Updat
Etoposide (VP-16) elicits apoptosis following prolonged G2-M cell arrest in p53-mutated human non-small cell lung cancer cells
Cancer Lett
Role of p21 in apoptosis and senescence of human colon cancer cells treated with camptothecin
J Biol Chem
Inhibition of telomerase activity by cisplatin in human testicular cancer cells
Eur J Cancer
Autophagic cell death, polyploidy and senescence induced in breast tumor cells by the substituted pyrrole JG-03-14, a novel microtubule poison
Biochem Pharmacol
Influence of p53 and caspase 3 activity on cell death and senescence in response to methotrexate in the breast tumor cell
Biochem Pharmacol
Cytostatic concentrations of anticancer agents do not affect telomerase activity of leukaemic cells in vitro
Eur J Cancer
Induction of telomerase activity and chromosome aberrations in human tumour cell lines following X-irradiation
Mutat Res
DNA topoisomerase II cleavage of telomeres in vitro and in vivo
Biochim Biophys Acta
The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability
Cell
Reversible manipulation of telomerase expression and telomere length. Implications for the ionizing radiation response and replicative senescence of human cells
J Biol Chem
Telomere length mediates the effects of telomerase on the cellular response to genotoxic stress
Exp Cell Res
Accumulation of checkpoint protein 53BP1 at DNA breaks involves its binding to phosphorylated histone H2AX
J Biol Chem
The two-stage mechanism controlling cellular senescence and immortalization
Exp Gerontol
A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy
Cell
Cellular senescence and cancer treatment
Biochim Biophys Acta
Non-targeted bystander effects induced by ionizing radiation
Mutat Res
The illusion of cell immortality
Br J Cancer
A biomarker that identifies senescent human cells in culture and in aging skin in vivo
Proc Natl Acad Sci USA
Oncogenes and senescence: breaking down in the fast lane
Genes Dev
A highly conserved repetitive DNA sequence, (TTAGGG)n, present at the telomeres of human chromosomes
Proc Natl Acad Sci USA
Telomeres shorten during ageing of human fibroblasts
Nature
Extension of life-span by introduction of telomerase into normal human cells
Science
Telomerase expression in human somatic cells does not induce changes associated with a transformed phenotype
Nat Genet
Shelterin: the protein complex that shapes and safeguards human telomeres
Genes Dev
Telomere dynamics: the means to an end
Cell Prolif
POT1 as a terminal transducer of TRF1 telomere length control
Nature
Protection of telomeres through independent control of ATM and ATR by TRF2 and POT1
Nature
Different telomere damage signaling pathways in human and mouse cells
EMBO J
p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2
Science
Erosion of the telomeric single-strand overhang at replicative senescence
Nat Genet
ATM and related protein kinases: safeguarding genome integrity
Nat Rev Cancer
Human cell senescence as a DNA damage response
Mech Ageing Dev
A DNA damage checkpoint response in telomere-initiated senescence
Nature
Cited by (239)
TGF-β, EMT, and resistance to anti-cancer treatment
2023, Seminars in Cancer BiologyThe Protective Effects of Silymarin on the Reproductive Toxicity: A Comprehensive Review
2023, Current Medicinal ChemistryExploring the role of senescence inducers and senotherapeutics as targets for anticancer natural products
2022, European Journal of PharmacologySorafenib, rapamycin, and venetoclax attenuate doxorubicin-induced senescence and promote apoptosis in HCT116 cells
2022, Saudi Pharmaceutical JournalDNA-PK inhibition by M3814 enhances chemosensitivity in non-small cell lung cancer
2021, Acta Pharmaceutica Sinica B
- 1
All three authors contributed equally to this manuscript and should be considered co-corresponding authors.