Growth arrest and cell death in the breast tumor cell in response to ionizing radiation and chemotherapeutic agents which induce DNA damage
Department of Pharmacology, Virginia Commonwealth University/Medical College of Virginia, Richmond 23298, USA. Breast Cancer Research and Treatment
(Impact Factor: 3.94).
09/2000; 62(3):223-35. DOI: 10.1023/A:1006414422919
Breast tumor cells are relatively refractory to apoptosis in response to modalities which induce DNA damage such as ionizing radiation and the topoisomerase II inhibitor, adriamycin. Various factors which may modulate the apoptotic response to DNA damage include the p53 status of the cell, levels and activity of the Bax and Bcl-2 families of proteins, activation of NF-kappa B, relative levels of insulin like growth factor and insulin-like growth factor binding proteins, activation of MAP kinases and PI3/Akt kinases, (the absence of) ceramide generation and the CD95 (APO1/Fas) signaling pathway. Prolonged growth arrest associated with replicative senescence may represent an alternative and reciprocal response to DNA-damage induced apoptosis that is p53 and/or p21waf1/cip1 dependent while delayed apoptosis may occur in p53 mutant breast tumor cells which fail to maintain the growth-arrested state. Clearly, the absence of an immediate apoptotic response to DNA damage does not eliminate other avenues leading to cell death and loss of self-renewal capacity in the breast tumor cell. Nevertheless, prolonged growth arrest (even if ultimately succeeded by apoptotic or necrotic cell death) could provide an opportunity for subpopulations of breast tumor cells to recover proliferative capacity and to develop resistance to subsequent clinical intervention.
Available from: Youhong Jiang
- "In the present study, SIRT1 showed an increased expression with low concentrations of drug treatment, but no altered expression at high concentrations. We propose that different drug concentrations may cause different degrees of cellular damage, which arouse various biological effects (31,32), and also that the SIRT1 pathway was activated only at the early phase of drug treatment at sub-lethal concentrations. It has been reported that biopsies from cancer patients treated with chemotherapeutic agents also expressed high levels of SIRT1 (33). "
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ABSTRACT: Silent mating-type information regulation 2, homolog 1 (SIRT1) represents an NAD(+)-dependent deacetylase that regulates the processes of stress response and cell survival. However, the functions of SIRT1 in stress- and drug-induced apoptosis remain elusive. The present study was designed to determine the effects of SIRT1 in tumor cells subjected to antitumor agent treatment and to identify the underlying mechanisms during the stress response. Several of the most commonly used antitumor medications [arsenic trioxide (As2O3), Taxol and doxorubicin (doxo)] were selected to treat MCF-7 human breast cancer cells with or without nicotinamide (NAM) inhibition. 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) was used to test cell viability. SIRT1 expression was tested by immunoblot analysis. The typical hallmarks of apoptosis (chromatin condensation, apoptotic bodies, sub G1 change and Annexin V(+)/PI(-) stained cells) were detected by Hoechst 33342 staining, flow cytometry and Annexin V(+)/PI(-) staining following NAM treatment. The cleavage of poly(ADP-ribose) polymerase (PARP) and caspases 9, 6 and 7 was detected through immunoblot analysis. Augmented SIRT1 expression was observed only at low concentrations (>80% cell viability) and the inhibition of SIRT1 deacetylase by NAM decreased the viability of the cancer cells exposed to low concentrations of antitumor agents. NAM induced typical apoptosis in the MCF-7 tumor cells, accompanied by the activation of the caspase cascade. SIRT1 promotes cellular survival at certain stress levels by its deacetylase function. The SIRT1 deacetylase inhibitor, NAM, triggers the activation of the caspase cascade and induces typical apoptosis in MCF-7 cells.
Available from: Ying Yan
- "It has been previously demonstrated that topo II poison treatment primarily results in a prolonged cell cycle arrest in most breast cancer cell lines studied . Additional studies in various types of cancer cells show that a portion of the cells that survive the topo II poison treatment ultimately develop a senescence-like phenotype (e.g. "
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ABSTRACT: Topo II poisons, which target topoisomerase II (topo II) to generate enzyme mediated DNA damage, have been commonly used for anti-cancer treatment. While clinical evidence demonstrate a capability of topo II poisons in inducing apoptosis in cancer cells, accumulating evidence also show that topo II poison treatment frequently results in cell cycle arrest in cancer cells, which was associated with subsequent resistance to these treatments. Results in this report indicate that treatment of MCF-7 and T47D breast cancer cells with topo II poisons resulted in an increased phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) and an subsequent induction of G2/M cell cycle arrest. Furthermore, inhibition of ERK1/2 activation using specific inhibitors markedly attenuated the topo II poison-induced G2/M arrest and diminished the topo II poison-induced activation of ATR and Chk1 kinases. Moreover, decreased expression of ATR by specific shRNA diminished topo II poison-induced G2/M arrest but had no effect on topo II poison-induced ERK1/2 activation. In contrast, inhibition of ERK1/2 signaling had little, if any, effect on topo II poison-induced ATM activation. In addition, ATM inhibition by either incubation of cells with ATM specific inhibitor or transfection of cells with ATM specific siRNA did not block topo II poison-induced G2/M arrest. Ultimately, inhibition of ERK1/2 signaling greatly enhanced topo II poison-induced apoptosis. These results implicate a critical role for ERK1/2 signaling in the activation of G2/M checkpoint response following topo II poison treatment, which protects cells from topo II poison-induced apoptosis.
Available from: Ying Yan
- "A growing amount of evidence shows that IR exposure of breast cancer cells frequently results in G2/M cell-cycle arrest , and induction of cell-cycle arrest after DNA damage has been associated with DNA repair and cell survival [50,59,60]. Thus, a better understanding of the mechanisms responsible for IR-induced G2/M cell-cycle arrest would potentially allow identifying novel therapeutic targets that could be exploited to sensitize breast cancer cells to radiation treatment. "
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ABSTRACT: In response to gamma-irradiation (IR)-induced double-strand DNA breaks, cells undergo cell-cycle arrest, allowing time for DNA repair before reentering the cell cycle. G2/M checkpoint activation involves activation of ataxia telangiectasia mutated (ATM)/ATM- and rad3-related (ATR) kinases and inhibition of Cdc25 phosphatases, resulting in inhibition of Cdc2 kinase and subsequent G2/M cell-cycle arrest. Previous studies from our laboratory showed that the G2/M checkpoint activation after IR exposure of MCF-7 breast cancer cells is dependent on the activation of extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) signaling. In the present studies, we investigated the role of Ras-related C3 botulinum toxin substrate 1 (Rac1) guanosine triphosphatase (GTPase) in IR-induced G2/M checkpoint response and ERK1/2 activation, as well as in cell survival after IR.
With Rac1-specific inhibitor, dominant negative mutant Rac1 (N17Rac1) and specific small interfering RNA, the effect of Rac1 on IR-induced G2/M checkpoint response and ERK1/2 activation was examined in human breast cancer cells. In addition, the effect of Rac1 on cell survival after irradiation was assessed by using Rac1-specific inhibitor.
IR exposure of MCF-7 breast cancer cells was associated with a marked activation of Rac1 GTPase. Furthermore, inhibition of Rac1 by using specific inhibitor, dominant-negative Rac1 mutant, or specific siRNA resulted in attenuation of IR-induced G2/M arrest and concomitant diminution of IR-induced activation of ATM, ATR, Chk1, and Chk2 kinases, as well as phosphorylation of Cdc2-Tyr15. Moreover, Rac1 inhibition or decreased Rac1 expression also abrogated IR-induced phosphorylation of mitogen-activated protein kinase kinase 1 and 2 (MEK1/2) and ERK1/2. Ultimately, inhibition of Rac1 markedly increased cellular sensitivity to IR exposure, which involves induction of apoptosis.
Studies in this report suggest that Rac1 GTPase plays an essential role in the activation of IR-induced ERK1/2 signaling and subsequent G2/M checkpoint response. Furthermore, results also support a role for Rac1 in promoting cell survival after irradiation treatment.
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