Telomeres and Telomerase Activity Are Regulated as a Complex System in Cultured Hepatoma Cells

Deschatrette, Jean; Lauga, J.; Maigne, J.; Wolfrom, C.

doi:10.1159/000076101

Cited by 4 publications

(14 citation statements)

References 28 publications

(25 reference statements)

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“…Non-linear, complex systems combine great flexibility and strong control of their evolution [32,33]. We showed previously that telomeres and telomerase activity behave as a complex system in hepatoma cells [16], which accounts for the maintenance of telomere length within a determined corridor of values. This is consistent with both the persistent proliferation and the recurrent episodes of drug resistance of these cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…Telomere lengths analysis and details of the methods were described previously [16]. Briefly, at each passage, DNA and cell extracts were prepared for telomere length analysis by Southern blotting.…”

Section: Telomere Length Analysismentioning

confidence: 99%

“…Fluctuations of MTRL, and their analysis, have been reported elsewhere [16]. Briefly, the range of MTRL was 8.98-10.37 kbp, with an oscillating pattern with three phases (Fig.…”

Section: Drugs Resistance and Proliferationmentioning

confidence: 99%

“…We observed alternating phases of cell sensitivity and resistance to each drug, lasting 2-3 months. We compared the kinetics of resistance to the previously reported patterns of cell proliferation [14] and telomere length [16]. Cell proliferation only partly correlated with drug resistance.…”

Section: Introductionmentioning

confidence: 99%

“…Filled columns: number of cells resistant to MTX (15 nM) per 5 Â 10 5 cells tested. On both diagrams, the line corresponds to mean telomere length[16].…”

mentioning

confidence: 99%

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Telomere dynamics determine episodes of anticancer drug resistance in rat hepatoma cells

Deschatrette

Kh²,

Gouthière³

et al. 2004

Anti-Cancer Drugs

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Clinical and experimental observations indicate that resistance to anticancer drugs may be spontaneously reversible over time, but the mechanisms of this reversal are unknown. The resistance of cultured hepatoma cells to methotrexate (MTX) and cisplatin was followed for 9 months. Cells were exposed to three treatments: MTX 200 nM for 24 h or 15 nM continuously and cisplatin 50 microM for 2 h. We investigated the relation between the temporal pattern of cell resistance and the previously reported fluctuations in cell proliferation rate, telomere length and telomerase activity. Spontaneous major peaks in resistance to each drug fell in time windows of 2-3 months (60-70 population doublings) and were at different times for each drug. The frequency of the fluctuations in drug resistance was the same as that of variations in cell growth rate, but amplitudes were unrelated. By contrast, resistance was directly related to telomere length dynamics in the same cells. MTX resistance occurred when telomeres shortened and cisplatin resistance when they were elongated. Furthermore, peaks of resistance to the continuous treatment with MTX were observed at 350-bp intervals of mean telomere length (9.06, 9.41, and 9.76 kbp) during the two 2-month phases of telomere shortening. Statistical analysis demonstrates the sinusoidal relationship between intermittent MTX resistance and telomere length. Possibly, erosion of telomeres encroaches on periodically spaced nucleosomal proteins, defining the onset of resistance phases. This evidence that resistance of tumoral cells to anticancer drugs may be intermittent and that onset of resistance is dictated by telomere length has major implications for clinical practice.

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Section: Discussionmentioning

confidence: 99%

Section: Telomere Length Analysismentioning

confidence: 99%

“…Fluctuations of MTRL, and their analysis, have been reported elsewhere [16]. Briefly, the range of MTRL was 8.98-10.37 kbp, with an oscillating pattern with three phases (Fig.…”

Section: Drugs Resistance and Proliferationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Filled columns: number of cells resistant to MTX (15 nM) per 5 Â 10 5 cells tested. On both diagrams, the line corresponds to mean telomere length[16].…”

mentioning

confidence: 99%

See 3 more Smart Citations

Telomere dynamics determine episodes of anticancer drug resistance in rat hepatoma cells

Deschatrette

Kh²,

Gouthière³

et al. 2004

Anti-Cancer Drugs

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Sinusoidal swinging dynamics of the telomere repair and cell growth activation functions of telomerase in rat liver cancer cells

et al. 2006

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Telomerase is a multimolecular complex of reverse transcriptase, RNA template, and regulatory proteins. It has two known functions: catalysis of the addition of [TTAGGG] repeats to telomeric DNA and the activation of various genes controlling cell proliferation. The possible coordination of these two functions is a key issue in understanding the growth of cancer cells. We report long-term changes to this complex system, as shown by specific data analysis methods. We show that the dynamics of the two functions of telomerase are tightly linked, with a change in predominant function every 13-14 weeks. The conservative behavior of this dynamic system probably accounts for the persistent proliferation of cancer cells.

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Unmasking Chaotic Attributes in Time Series of Living Cell Populations

2010

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BackgroundLong-range oscillations of the mammalian cell proliferation rate are commonly observed both in vivo and in vitro. Such complicated dynamics are generally the result of a combination of stochastic events and deterministic regulation. Assessing the role, if any, of chaotic regulation is difficult. However, unmasking chaotic dynamics is essential for analysis of cellular processes related to proliferation rate, including metabolic activity, telomere homeostasis, gene expression, and tumor growth.Methodology/Principal FindingsUsing a simple, original, nonlinear method based on return maps, we previously found a geometrical deterministic structure coordinating such fluctuations in populations of various cell types. However, nonlinearity and determinism are only necessary conditions for chaos; they do not by themselves constitute a proof of chaotic dynamics. Therefore, we used the same analytical method to analyze the oscillations of four well-known, low-dimensional, chaotic oscillators, originally designed in diverse settings and all possibly well-adapted to model the fluctuations of cell populations: the Lorenz, Rössler, Verhulst and Duffing oscillators. All four systems also display this geometrical structure, coordinating the oscillations of one or two variables of the oscillator. No such structure could be observed in periodic or stochastic fluctuations.Conclusion/SignificanceTheoretical models predict various cell population dynamics, from stable through periodically oscillating to a chaotic regime. Periodic and stochastic fluctuations were first described long ago in various mammalian cells, but by contrast, chaotic regulation had not previously been evidenced. The findings with our nonlinear geometrical approach are entirely consistent with the notion that fluctuations of cell populations can be chaotically controlled.

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Telomeres and Telomerase Activity Are Regulated as a Complex System in Cultured Hepatoma Cells

Cited by 4 publications

References 28 publications

Telomere dynamics determine episodes of anticancer drug resistance in rat hepatoma cells

Telomere dynamics determine episodes of anticancer drug resistance in rat hepatoma cells

Sinusoidal swinging dynamics of the telomere repair and cell growth activation functions of telomerase in rat liver cancer cells

Unmasking Chaotic Attributes in Time Series of Living Cell Populations

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