Arsenite induces prominent mitotic arrest via inhibition of G2 checkpoint activation in CGL-2 cells

Yih, Ling-Huei; Hsueh, Shun‐Wen; Luu, Wei-Shu; Chiu, Ted H.; Lee, Te‐Chang

doi:10.1093/carcin/bgh295

Cited by 54 publications

(54 citation statements)

References 44 publications

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“…Another group has also shown that arsenic treatment induces the phosphorylation and nuclear accumulation of histone H2AX (28). However, our data indicated the colocalization and direct involvement of TOPK in As 3+ -induced apoptosis.…”

Section: Discussioncontrasting

confidence: 62%

Lymphokine-Activated Killer T-Cell-Originated Protein Kinase Phosphorylation of Histone H2AX Prevents Arsenite-Induced Apoptosis in RPMI7951 Melanoma Cells

Zykova

Zhu

et al. 2006

Clinical Cancer Research

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Purpose: Arsenic is a valuable therapeutic tool in cancer treatment. Lymphokine-activated killer T-cell-originated protein kinase (TOPK) is highly expressed in cancer cells, but its specific function is still unknown. We investigated the role of TOPK in arsenic-induced apoptosis in RPMI7951human melanoma cells. Experimental Design: Expression of TOPK was evaluated in different melanoma cell lines, and liquid chromatography-tandem mass spectrometry analysis was used to identify proteins binding with TOPK. Immunofluorescence, Western blot, and flow cytometry were used to assess the effect of arsenic onTOPK, histone H2AX, and apoptosis in RPMI7951cells. Results: Melanoma cell lines expressing high levels of TOPK were more resistant to arsenite (As 3+ )-induced apoptosis. As 3+ treatment induced phosphorylation of TOPK and histone H2AX in RPMI7951human melanoma cells. Liquid chromatography-tandem mass spectrometry results indicated thatTOPK could bind with histone H2AX, and in vitro and in vivo assays confirmed that TOPK binds with and phosphorylates histone H2AX. As 3+ treatment caused phosphorylation of TOPK, which colocalized with phosphorylated histone H2AX in the nucleus. TOPK small interfering RNA cells exhibited a decreased phosphorylation of histone H2AX with As 3+ treatment. As 3+ -induced apoptosis was decreased in H2AX À/À cells but increased in TOPK small interfering RNA cells. Conclusions: TOPK binds with histone H2AX and inhibits As 3+ -induced apoptosis through phosphorylation of histone H2AX. Melanoma cell lines with high levels ofTOPK are more resistant to As 3+ -induced apoptosis. Therefore, inhibition of TOPK activity combined with As 3+ treatment may be helpful in the treatment of melanomas.

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Section: Discussioncontrasting

confidence: 62%

Lymphokine-Activated Killer T-Cell-Originated Protein Kinase Phosphorylation of Histone H2AX Prevents Arsenite-Induced Apoptosis in RPMI7951 Melanoma Cells

Zykova

Zhu

et al. 2006

Clinical Cancer Research

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“…Although the linkage between p53 mutation and arsenic exposure is not clear, the affect of arsenic on p53 regulation is well documented. Both in vitro and As-BD lesion studies indicated that arsenic exposure was associated with G2/M cell cycle arrest and DNA aneuploidy [88][89][90]. These cellular abnormalities may associate with p53 dysfunction induced by arsenic.…”

Section: Pathomechanisms Of Arsenic-induced Bowen's Diseasementioning

confidence: 99%

Arsenic Carcinogenesis in the Skin

2006

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SummaryChronic arsenic poisoning is a world public health issue. Long-term exposure to inorganic arsenic (As) from drinking water has been documented to induce cancers in lung, urinary bladder, kidney, liver and skin in a dose-response relationship. Oxidative stress, chromosomal abnormality and altered growth factors are possible modes of action in arsenic carcinogenesis. Arsenic tends to accumulate in the skin. Skin hyperpigmentation and hyperkeratosis have long been known to be the hallmark signs of chronic As exposure. There are significant associations between these dermatological lesions and risk of skin cancer. The most common arsenic-induced skin cancers are Bowen's disease (carcinoma in situ), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Arsenic-induced Bowen's disease (As-BD) is able to transform into invasive BCC and SCC. Individuals with As-BD are considered for more aggressive cancer screening in the lung and urinary bladder. As-BD provides an excellent model for studying the early stages of chemical carcinogenesis in human beings. Arsenic exposure is associated with G2/M cell cycle arrest and DNA aneuploidy in both cultured keratinocytes and As-BD lesions. These cellular abnormalities relate to the p53 dysfunction induced by arsenic. The characteristic clinical figures of arsenic-induced skin cancer are: (i) occurrence on sun-protected areas of the body; (ii) multiple and recrudescent lesions. Both As and UVB are able to induce skin cancer. Arsenic treatment enhances the cytotoxicity, mutagenicity and clastogenicity of UV in mammalian cells. Both As and UVB induce apoptosis in keratinocytes by caspase-9 and caspase-8 signaling, respectively. Combined UVB and As treatments resulted in the antiproliferative and proapoptotic effects by stimulating both caspase pathways in the keratinocytes. UVB irradiation inhibited mutant p53 and ki-67 expression, as well as increased in the number of apoptotic cells in As-BD lesions which resulted in an inhibitory effect on proliferation. As-UVB interaction provides a reasonable explanation for the rare occurrences of arsenical cancer in the sun-exposed skin. The multiple and recurrent skin lesions are associated with cellular immune dysfunction in chronic arsenism. A decrease in peripheral CD4+ cells was noticed in the inhabitants of arsenic exposure areas. There was a decrease in the number of Langerhans cells in As-BD lesion which results in an impaired immune function on the lesional sites. Since CD4+ cells are the target cell affected by As, the interaction between CD4+ cells and epidermal keratinocytes under As affection might be closely linked to the pathogenesis of multiple occurrence of arsenic-induced skin cancer. In this

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“…Arsenite is a mitotic disruptor causing mitotic arrest and subsequent apoptosis in SV40-transformed human fibroblast (States et al, 2002), TR9-7 cells , HeLa, KB (Huang and Lee, 1998), CGL-2 (Yih et al, 2005), and U937 (McCabe, Jr. et al, 2000;McCollum et al, 2005) cells. The mechanism through which arsenite causes mitotic arrest is highly disputed.…”

Section: Introductionmentioning

confidence: 99%

Arsenite-induced mitotic death involves stress response and is independent of tubulin polymerization

Taylor

McNeely

Miller

et al. 2008

Toxicology and Applied Pharmacology

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Arsenite, a known mitotic disruptor, causes cell cycle arrest and cell death at anaphase. The mechanism causing mitotic arrest is highly disputed. We compared arsenite to the spindle poisons nocodazole and paclitaxel. Immunofluorescence analysis of α-tubulin in interphase cells demonstrated that, while nocodazole and paclitaxel disrupt microtubule polymerization through destabilization and hyperpolymerization, respectively, microtubules in arsenite-treated cells remain comparable to untreated cells even at supra-therapeutic concentrations. Immunofluorescence analysis of α-tubulin in mitotic cells showed spindle formation in arsenite-and paclitaxel-treated cells but not in nocodazole-treated cells. Spindle formation in arsenite-treated cells appeared irregular and multi-polar. γ-tubulin staining showed that cells treated with nocodazole and therapeutic concentrations of paclitaxel contained two centrosomes. In contrast, most arsenite-treated mitotic cells contained more than two centrosomes, similar to centrosome abnormalities induced by heat shock. Of the three drugs tested, only arsenite treatment increased expression of the inducible isoform of heat shock protein 70 (HSP70i). HSP70 and HSP90 proteins are intimately involved in centrosome regulation and mitotic spindle formation. HSP90 inhibitor 17-DMAG sensitized cells to arsenite treatment and increased arsenite-induced centrosome abnormalities. Combined treatment of 17-DMAG and arsenite resulted in a supra-additive effect on viability, mitotic arrest, and centrosome abnormalities. Thus, arsenite-induced abnormal centrosome amplification and subsequent mitotic arrest is independent of effects on tubulin polymerization and may be due to specific stresses that are protected against by HSP90 and HSP70.

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Arsenite induces prominent mitotic arrest via inhibition of G2 checkpoint activation in CGL-2 cells

Cited by 54 publications

References 44 publications

Lymphokine-Activated Killer T-Cell-Originated Protein Kinase Phosphorylation of Histone H2AX Prevents Arsenite-Induced Apoptosis in RPMI7951 Melanoma Cells

Lymphokine-Activated Killer T-Cell-Originated Protein Kinase Phosphorylation of Histone H2AX Prevents Arsenite-Induced Apoptosis in RPMI7951 Melanoma Cells

Arsenic Carcinogenesis in the Skin

Arsenite-induced mitotic death involves stress response and is independent of tubulin polymerization

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