Selective Pharmacologic Inhibition of c-Jun NH<sub>2</sub>-Terminal Kinase Radiosensitizes Thyroid Anaplastic Cancer Cell Lines via Induction of Terminal Growth Arrest

Bulgin, Dmitry; Podtcheko, Alexei; Takakura, Shu; Mitsutake, Norisato; Namba, Hiroyuki; Saenko, Vladimir; Ohtsuru, Akira; Rogounovitch, Tatiana; Palona, Iryna; Yamashita, Shunichi

doi:10.1089/thy.2006.16.217

Cited by 14 publications

(13 citation statements)

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“…Here, we show that the combined treatment of SP600125 and IR resulted in inhibition of cell proliferation through synergistic induction of premature senescence, indicating that SP600125 could be combined with radiotherapy or other chemotherapeutic drugs in treating cancer. Our results concur with the report that showed the effectiveness of combined pharmacological interference using the JNK inhibitor with radiotherapy in treating thyroid cancer (Bulgin et al, 2006).…”

Section: Discussionsupporting

confidence: 93%

Prevention of premature senescence requires JNK regulation of Bcl-2 and reactive oxygen species

Lee

et al. 2009

Oncogene

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Premature senescence is considered as a cellular defense mechanism to prevent tumorigenesis. Although recent evidences show that c-Jun N-terminal kinase (JNK) is involved in the senescence process, the mechanism for this regulation is not fully understood. Here, we examined the role of JNK in premature senescence of tumor cells. Treatment of cells with the JNK-specific inhibitor SP600125 caused phenotypical changes of senescence and triggered a rapid increase in mitochondrial reactive oxygen species (ROS) production and DNA-damage response (DDR) in MCF7 breast carcinoma cells. ROS generation was attributed to the suppression of B-cell lymphoma-2 (Bcl-2) phosphorylation, and resulted in DNA damage and p53 activation. Bax did not change their localization to the mitochondria, which is required for apoptosis. The essential roles of JNK and phosphorylated Bcl-2 in preventing premature senescence were confirmed using RNA interference and ectopic expression of mutants of Bcl-2, including phosphomimetic and nonphosphorylatable forms. These findings were evidenced in H460 lung carcinoma cells and primary human embryonic fibroblasts. Altogether, our results showed that loss of JNK activity triggers a Bcl-2/ROS/DDR signaling cascade that ultimately leads to premature senescence, indicating that basal JNK activity is essential in preventing premature senescence.

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Section: Discussionsupporting

confidence: 93%

Prevention of premature senescence requires JNK regulation of Bcl-2 and reactive oxygen species

Lee

et al. 2009

Oncogene

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“…Tumor cells in G 2 -M are highly sensitive to radiation (43). In fact, pharmacologic inhibition of JNKs has been reported to inhibit the repair of radiation-induced DNA damage and to increase radiation sensitivity (44). Both cisplatin and radiation, which are commonly used in combination for treatment of HNSCC, may be efficacious in cell killing in the S phase (45,46).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Jun NH2-Terminal Kinases Suppresses the Growth of Experimental Head and Neck Squamous Cell Carcinoma

Gross

Boyle²,

et al. 2007

Clinical Cancer Research

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Purpose: This study was carried out to investigate whether c-Jun NH 2 -terminal kinases (JNK) are potential targets for treating head and neck squamous cell carcinoma (HNSCC). Experimental Design: JNK activity was first evaluated in 20 paired samples of human HNSCC. The antitumor activity of SP600125, a reversible nonselective ATP-competitive inhibitor of JNKs, was then investigated both in an HNSCC xenograft model and in vitro using immunohistochemistry, immunoblotting, enzyme immunoassay, flow cytometry, and a Matrigel assay of capillary tube formation. Complementary studies were carried out using small interfering RNA to JNK1/2. Results: JNK activity was increased in human HNSCC compared with normal-appearing epithelium. Treatment of mice bearing HNSCC xenografts with SP600125 resulted in >60% inhibition of tumor growth relative to vehicle-treated animals. Inhibition of tumor growth was associated with significant reductions in both cell proliferation and microvessel density. SP600125 inhibited tumor cell proliferation by causing delays in both the S and G 2 -M phases of the cell cycle. Inhibition of angiogenesis seemed to reflect effects on both tumor and endothelial cells. The JNK inhibitor suppressed the production of vascular endothelial growth factor and interleukin-8 by tumor cells and also inhibited endothelial cell proliferation and capillary tube formation. Reduced amounts and phosphorylation of epidermal growth factor receptor were found in tumor cells after treatment with SP600125. Small interfering RNA^mediated suppression of JNK1/2 led to reduced tumor cell proliferation and decreased levels of epidermal growth factor receptor, vascular endothelial growth factor, and interleukin-8. Conclusions: JNK activity is commonly increased in HNSCC. Our preclinical results provide a rationale for evaluating JNK inhibition as an approach to treating HNSCC.

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“…Cells were fixed with 2% formaldehyde and 0.2% glutalaldehyde and assayed for SA-β-gal activity using X-gal (5-bromo-4-chloro-3-indolyl β-D-galactosidase) at pH 6.0, as described previously. (24,25) SA-β-gal-positive cells were detected by bright-field microscopy. The percentages of positive cells were determined by scoring approximately 200-400 cells/field for each sample.…”

Section: Real-time Reverse Transcription-polymerase Chain Reaction (Rmentioning

confidence: 99%

Oncogenic role of miR‐17‐92 cluster in anaplastic thyroid cancer cells

Takakura

Mitsutake

Nakashima³

et al. 2008

Cancer Science

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(1) Mature miRNAs, ranging from 18 to 25 nucleotides in length, processed by two-step cleavage involving Drosha and Dicer are thought to negatively regulate messenger RNA (mRNA). The mature miRNA binds to target mRNA and induces its cleavage or translational repression depending on the degree of complementarity.(2) Although hundreds of miRNAs have been already cloned, only a small number of them have been characterized.Recently, several miRNAs have been reported to be involved in cell proliferation or apoptosis in various types of cancers. (3,4) MiR-15a and miR-16 induce apoptosis by targeting BCL2, and these miRNAs are frequently deleted or underexpressed in chronic lymphocytic leukemia.(5) Let-7 expression is reduced in lung cancer with poor prognosis, (6) and inversely correlates with expression of RAS protein, suggesting a possible mechanism for cancer cell proliferation.(7) Compared to these underexpressed miRNAs, miR-21 has an antiapoptotic function and is overexpressed in glioblastoma. Knockdown of miR-21 in glioblastoma cells induced caspase activation, resulting in apoptotic cell death.(8) Thus, miRNAs can act as both tumor suppressor and oncogene.The miR-17-92 cluster, composed of seven miRNAs (miR-17-5p, miR-17-3p, miR-18a, miR-19a, miR-20a, miR-19b, and miR-92-1) and located in intron 3 of the C13orf25 gene, is overexpressed in lung cancer and B-cell lymphoma.(9,10) Enforced expression of truncated clusters comprising miR-17-5p~19b (miR-17-19b), the vertebrate-specific portion of the miR-17-92 cluster, accelerated tumor development in a mouse B-cell lymphoma model, suggesting oncogenic function of miR-17-19b. On the other hand, O'Donnell et al. have reported that expression of oncogenic E2F1 is negatively regulated by miR-17-5p and miR-20a, members of the cluster, implying that they act as a tumor suppressors.(11) Thus, the function of the cluster is still controversial.In thyroid cancer, overexpression of several miRNAs has been reported. He et al. have reported that three miRNAs (miR-221, miR-222, and miR-146) are overexpressed in papillary thyroid carcinomas (PTC) and regulate KIT expression.(12) Another group has also shown that miR-221, miR-222 and miR-181b are overexpressed in PTC, and inhibition of miR-221 by antisense oligonucleotides led to attenuation of cell growth.(13) In follicular thyroid cancers (FTC), miR-197 and miR-346 are significantly overexpressed. (14) In vitro overexpression of either miRNA induced cell proliferation, whereas inhibition led to growth arrest. Very recently, Visone et al. have reported that significant decrease in miR-30d, miR-125b, miR-26a, and miR-30a-5p was detected in human anaplastic thyroid cancers (ACT). (15) ATC are highly aggressive and fatal tumors with less than 8 months of mean survival after diagnosis.(16) Various treatment patterns including radiation and chemotherapy have been tried in ATC, but they are mostly unsuccessful.(17) Therefore, the identification of miRNAs involved in proliferation or apoptosis in ATC cells has important therapeutic imp...

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Selective Pharmacologic Inhibition of c-Jun NH₂-Terminal Kinase Radiosensitizes Thyroid Anaplastic Cancer Cell Lines via Induction of Terminal Growth Arrest

Abstract: JNK signaling is an essential component of ATC cell proliferation and survival after radiation therapy. Hence, pharmacological interference with JNK pathway in combination with radiotherapy may be a promising treatment of ATC.

Cited by 14 publications

References 38 publications

Prevention of premature senescence requires JNK regulation of Bcl-2 and reactive oxygen species

Prevention of premature senescence requires JNK regulation of Bcl-2 and reactive oxygen species

Inhibition of Jun NH2-Terminal Kinases Suppresses the Growth of Experimental Head and Neck Squamous Cell Carcinoma

Oncogenic role of miR‐17‐92 cluster in anaplastic thyroid cancer cells

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Selective Pharmacologic Inhibition of c-Jun NH2-Terminal Kinase Radiosensitizes Thyroid Anaplastic Cancer Cell Lines via Induction of Terminal Growth Arrest

Abstract: JNK signaling is an essential component of ATC cell proliferation and survival after radiation therapy. Hence, pharmacological interference with JNK pathway in combination with radiotherapy may be a promising treatment of ATC.

Cited by 14 publications

References 38 publications

Prevention of premature senescence requires JNK regulation of Bcl-2 and reactive oxygen species

Prevention of premature senescence requires JNK regulation of Bcl-2 and reactive oxygen species

Inhibition of Jun NH2-Terminal Kinases Suppresses the Growth of Experimental Head and Neck Squamous Cell Carcinoma

Oncogenic role of miR‐17‐92 cluster in anaplastic thyroid cancer cells

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Selective Pharmacologic Inhibition of c-Jun NH₂-Terminal Kinase Radiosensitizes Thyroid Anaplastic Cancer Cell Lines via Induction of Terminal Growth Arrest