Heat shock induces centrosomal dysfunction, and causes non-apoptotic mitotic catastrophe in human tumour cells

Nakahata, Keiji; Miyakoda, Mana; Suzuki, Keiji; Kodama, Seiji; Watanabe, Masami

doi:10.1080/02656730210129736

Cited by 45 publications

(40 citation statements)

References 32 publications

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“…Heat shock-mediated denaturation of key proteins in critical pathways affects many cellular functions. We surveyed several pathways known to be affected by heat shock and irradiation (23)(24)(25)(26)(27)(28)(29). Loss of mitochondrial membrane potential (Dw m ), an important initiator of cell death signaling (30,31), can be a consequence of heat shocks capable of denaturing protein and activating Hsf1 (23).…”

Section: Resultsmentioning

confidence: 99%

Novel Chemical Enhancers of Heat Shock Increase Thermal Radiosensitization through a Mitotic Catastrophe Pathway

et al. 2007

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Radiation therapy combined with adjuvant hyperthermia has the potential to provide outstanding local-regional control for refractory disease. However, achieving therapeutic thermal dose can be problematic. In the current investigation, we used a chemistry-driven approach with the goal of designing and synthesizing novel small molecules that could function as thermal radiosensitizers..2]octan-3-ol was identified as a compound that could lower the threshold for Hsf1 activation and thermal sensitivity. Enhanced thermal sensitivity was associated with significant thermal radiosensitization. We established the structural requirements for activity: the presence of an N-benzenesulfonylindole or N-benzylindole moiety linked at the indolic 3-position to a 2-(1-azabicyclo[2.2.2]octan-3-ol) or 2-(1-azabicyclo[2.2.2]octan-3-one) moiety. These small molecules functioned by exploiting the underlying biophysical events responsible for thermal sensitization. Thermal radiosensitization was characterized biochemically and found to include loss of mitochondrial membrane potential, followed by mitotic catastrophe. These studies identified a novel series of small molecules that represent a promising tool for the treatment of recurrent tumors by ionizing radiation. [Cancer Res 2007;67(2):695-701]

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Section: Resultsmentioning

confidence: 99%

Novel Chemical Enhancers of Heat Shock Increase Thermal Radiosensitization through a Mitotic Catastrophe Pathway

et al. 2007

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“…HeLa nor K-562 cells increased expression of genes characteristically expressed in the G2/M phases of the cell cycle genes after 10 h of heat shock, suggesting a G2/M cell cycle arrest ( Figure 4D). It was previously reported that heat shock causes a transient G2/M arrest in primary cell lines, but not in many cancer cell lines (Nakahata et al, 2002).…”

Section: Heat Shockmentioning

confidence: 99%

Diverse and Specific Gene Expression Responses to Stresses in Cultured Human Cells

Murray

Whitfield

Trinklein

et al. 2004

MBoC

276

236

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We used cDNA microarrays in a systematic study of the gene expression responses of HeLa cells and primary human lung fibroblasts to heat shock, endoplasmic reticulum stress, oxidative stress, and crowding. Hierarchical clustering of the data revealed groups of genes with coherent biological themes, including genes that responded to specific stresses and others that responded to multiple types of stress. Fewer genes increased in expression after multiple stresses than in free-living yeasts, which have a large general stress response program. Most of the genes induced by multiple diverse stresses are involved in cell-cell communication and other processes specific to higher organisms. We found substantial differences between the stress responses of HeLa cells and primary fibroblasts. For example, many genes were induced by oxidative stress and dithiothreitol in fibroblasts but not HeLa cells; conversely, a group of transcription factors, including c-fos and c-jun, were induced by heat shock in HeLa cells but not in fibroblasts. The dataset is freely available for search and download at http://microarray-pubs.stanford.edu/human_stress/Home.shtml.

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“…It is well known that the onset of nuclear fragmentation is a hallmark of mitotic catastrophe (36). Mitotic catastrophe is distinguishable from apoptosis because it lacks DNA degradation that can be observed by either DNA laddering on agarose gel or TUNEL staining (37). To test whether increased mitotic catastrophe is the cause of increased toxicity in M2 cells, cells displaying nuclear fragmentation were scored at various time points after irradiation.…”

Section: Filamin-a and G 2 Arrestmentioning

confidence: 99%

Recovery from DNA Damage-induced G2 Arrest Requires Actin-binding Protein Filamin-A/Actin-binding Protein 280

Meng

Yuan

Maestas

et al. 2004

Journal of Biological Chemistry

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Filamin-A (filamin-1) is an actin-binding protein involved in the organization of actin networks. Our previous study shows that filamin-A interacts with BRCA2, and lack of filamin-A expression results in increased cellular sensitivity to several DNA damaging agents in melanoma cells (Yuan, Y., and Shen, Z. (2001) J. Biol. Chem. 276, 48318 -48324), suggesting a role of filamin-A in DNA damage response. In this report, we demonstrated that deficiency of filamin-A results in an 8-h delay in the recovery from G 2 arrest in response to ionizing radiation. However, filamin-A deficiency does not affect the initial activation of the G 2 /M checkpoint. We also found that filamin-A deficiency results in sustained activation of Chk1 and Chk2 after irradiation. This in turn causes a delay in the dephosphorylation of phospho-Cdc2, which is inhibitory to the G 2 /M transition. In addition, filamin-A-deficient M2 cells undergo mitotic catastrophe-related nuclear fragmentation after they are released from the G 2 arrest. Together, these data suggest a functional role of filamin-A in the recovery from G 2 arrest and subsequent mitotic cell death after DNA damage.In response to DNA damage, cell cycle checkpoints are activated to delay or block the progression of the cell cycle. This may prevent damaged cells from progressing into the next phase of the cell cycle, thus facilitating the maintenance of genomic stability (1-4). When DNA damage is repaired, cells recover from cell cycle arrest and resume their normal cell cycle progression. Studies in yeast suggest that the transition from cell cycle arrest to cell cycle progression is not simply a passive response to the removal of DNA damage. It appears to be an active process in which cells can adapt to prolonged cell cycle arrest even when the DNA damage has not been completely repaired (5-8). However, the mechanism that regulates the recovery of cell cycle arrest is poorly understood, especially in mammalian cells.Our previous study has shown that an actin-binding protein filamin-A (filamin-1, FLNa, 1 or ABP-280) interacts with BRCA2, and deficiency of filamin-A renders melanoma cells more sensitive to ␥-rays, bleomycin, and UV irradiation (9). In this study, we further investigated the role of filamin-A in cell cycle regulation using a filamin-A-deficient melanoma cell line (M2) and a C8161 melanoma cell line in which filamin-A expression was knocked down by RNA interference. We found that filamin-A deficiency correlated with an approximate 8-h delay in the recovery from G 2 arrest after irradiation. However, filamin-A deficiency had little effect on the initiation of G 2 arrest, indicating intact activation of the G 2 /M checkpoint. The delayed G 2 recovery correlated with delayed dephosphorylation of the phospho-Cdc2 protein and sustained activation of the Chk1 and Chk2 kinases. Furthermore, we found that deficiency of filamin-A renders cells more prone to mitotic cell death. These data provide the first evidence that filamin-A plays a significant role in the recovery from rad...

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Heat shock induces centrosomal dysfunction, and causes non-apoptotic mitotic catastrophe in human tumour cells

Cited by 45 publications

References 32 publications

Novel Chemical Enhancers of Heat Shock Increase Thermal Radiosensitization through a Mitotic Catastrophe Pathway

Novel Chemical Enhancers of Heat Shock Increase Thermal Radiosensitization through a Mitotic Catastrophe Pathway

Diverse and Specific Gene Expression Responses to Stresses in Cultured Human Cells

Recovery from DNA Damage-induced G2 Arrest Requires Actin-binding Protein Filamin-A/Actin-binding Protein 280

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