Elsevier

Biochemical Pharmacology

Volume 76, Issue 8, 15 October 2008, Pages 947-957
Biochemical Pharmacology

Commentary
Accelerated senescence: An emerging role in tumor cell response to chemotherapy and radiation

https://doi.org/10.1016/j.bcp.2008.06.024Get rights and content

Abstract

Treatment of malignancies with chemotherapeutic drugs and/or radiotherapy is designed to eliminate the disease by depriving the tumor cell of its reproductive potential. Frequently, the desired effect of cell killing is achieved through the promotion of apoptosis; however, accumulating evidence suggests that apoptosis may not be the exclusive or even primary mechanism whereby tumor cells lose their self-renewal capacity after radiation or drug treatment, particularly in the case of solid tumors. While failure to undergo apoptosis in response to chemotherapeutic drugs or radiation may represent a mechanism of drug and radiation resistance, particularly in the case of leukemias and lymphomas, it is gradually being recognized that in the case of solid tumors, loss of reproductive capacity can occur through alternative pathways including reproductive cell death or mitotic catastrophe, through autophagic cell death, and as described below, through a terminally arrested state similar to replicative senescence.

Studies building upon the phenomenon of replicative senescence in normal cells approaching the limit of their reproductive potential have identified a comparable senescence-like arrest as a component of the tumor cell response to chemotherapeutic drugs and radiation. This response, which has been termed “premature senescence”, “senescence-like growth arrest”, “stress-induced premature senescence”, and “accelerated senescence”, can also result from supraphysiological mitogenic signaling, sub-optimal culture conditions, and ectopic expression of oncogenes. Here, we will use the term “accelerated senescence” in our consideration of the morphological, biochemical, and molecular aspects of treatment-induced senescence, its relationship to classical replicative senescence, its prevalence in clinical specimens and the implications of accelerated senescence for the outcome of cancer therapy.

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

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    All three authors contributed equally to this manuscript and should be considered co-corresponding authors.

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