p73 Protein Expression Correlates With Radiation-Induced Apoptosis in the Lack of p53 Response to Radiation Therapy for Cervical Cancer

Wakatsuki, Masaru; Ohno, Tatsuya; Iwakawa, Mayumi; Ishikawa, Hitoshi; Noda, Shuhei; Ohta, Toshie; Kato, Shingo; Tsujii, Hirohiko; Imai, Takashi; Nakano, Takashi

doi:10.1016/j.ijrobp.2007.08.033

Cited by 19 publications

(15 citation statements)

References 34 publications

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“…It seemed like that the radioresistance of glioma cells was mainly due to the regulation at the later stage. Therefore, in spite of the fact that a significant status of p53 regulation in the radioresistance mechanism, 8, 9, 10, 11, 14, 18, 24, 45 more studies are needed.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome analysis of glioma cells for the dynamic response to γ-irradiation and dual regulation of apoptosis genes: a new insight into radiotherapy for glioblastomas

Rao

Wang

et al. 2013

Cell Death Dis

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Ionizing radiation (IR) is of clinical importance for glioblastoma therapy; however, the recurrence of glioma characterized by radiation resistance remains a therapeutic challenge. Research on irradiation-induced transcription in glioblastomas can contribute to the understanding of radioresistance mechanisms. In this study, by using the total mRNA sequencing (RNA-seq) analysis, we assayed the global gene expression in a human glioma cell line U251 MG at various time points after exposure to a growth arrest dose of γ-rays. We identified 1656 genes with obvious changes at the transcriptional level in response to irradiation, and these genes were dynamically enriched in various biological processes or pathways, including cell cycle arrest, DNA replication, DNA repair and apoptosis. Interestingly, the results showed that cell death was not induced even many proapoptotic molecules, including death receptor 5 (DR5) and caspases were activated after radiation. The RNA-seq data analysis further revealed that both proapoptosis and antiapoptosis genes were affected by irradiation. Namely, most proapoptosis genes were early continually responsive, whereas antiapoptosis genes were responsive at later stages. Moreover, HMGB1, HMGB2 and TOP2A involved in the positive regulation of DNA fragmentation during apoptosis showed early continual downregulation due to irradiation. Furthermore, targeting of the TRAIL/DR5 pathway after irradiation led to significant apoptotic cell death, accompanied by the recovered gene expression of HMGB1, HMGB2 and TOP2A. Taken together, these results revealed that inactivation of proapoptotic signaling molecules in the nucleus and late activation of antiapoptotic genes may contribute to the radioresistance of gliomas. Overall, this study provided novel insights into not only the underlying mechanisms of radioresistance in glioblastomas but also the screening of multiple targets for radiotherapy.

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Section: Discussionmentioning

confidence: 99%

Transcriptome analysis of glioma cells for the dynamic response to γ-irradiation and dual regulation of apoptosis genes: a new insight into radiotherapy for glioblastomas

Rao

Wang

et al. 2013

Cell Death Dis

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“…Whether p73 is required for radiation-induced p53-independent apoptosis is not known, but available data suggest this is the case. p73 expression correlates with the level of radiation-induced apoptosis in the absence of p53 in tumor samples of human cervical cancer patients [6]. Forced expression of p73 in human vestibular schwannoma cells also sensitized cells to ionizing radiation-induced apoptosis [7].…”

Section: Introductionmentioning

confidence: 99%

Genome-Wide Expression Analysis Identifies a Modulator of Ionizing Radiation-Induced p53-Independent Apoptosis in Drosophila melanogaster

et al. 2012

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Tumor suppressor p53 plays a key role in DNA damage responses in metazoa, yet more than half of human tumors show p53 deficiencies. Therefore, understanding how therapeutic genotoxins such as ionizing radiation (IR) can elicit DNA damage responses in a p53-independent manner is of clinical importance. Drosophila has been a good model to study the effects of IR because DNA damage responses as well as underlying genes are conserved in this model, and because streamlined gene families make loss-of-function analyses feasible. Indeed, Drosophila is the only genetically tractable model for IR-induced, p53-independent apoptosis and for tissue regeneration and homeostasis after radiation damage. While these phenomenon occur only in the larvae, all genome-wide gene expression analyses after irradiation to date have been in embryos. We report here the first analysis of IR-induced, genome-wide gene expression changes in wild type and p53 mutant Drosophila larvae. Key data from microarrays were confirmed by quantitative RT-PCR. The results solidify the central role of p53 in IR-induced transcriptome changes, but also show that nearly all changes are made of both p53-dependent and p53-independent components. p53 is found to be necessary not just for the induction of but also for the repression of transcript levels for many genes in response to IR. Furthermore, Functional analysis of one of the top-changing genes, EF1a-100E, implicates it in repression of IR-induced p53-independent apoptosis. These and other results support the emerging notion that there is not a single dominant mechanism but that both positive and negative inputs collaborate to induce p53-independent apoptosis in response to IR in Drosophila larvae.

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“…Their results support that patients with low p27 protein expression have worse prognosis than others, indicating that p27 may participate in the progression of cervical SCC [84]. Recent results suggested that p73, an other protein related to the p53 protein, may also play an important role in compensating for the lack of p53 function in RT-induced apoptosis of cervical cancer [85].…”

Section: Introductionmentioning

confidence: 73%

Molecular profiling of uterine cervix carcinoma: an overview with a special focus on rationally designed target-based anticancer agents

Magné

Chargari

Deutsch

et al. 2008

Cancer Metastasis Rev

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Although conventional multimodality approaches allowed improvement in the prognosis of patients with cervix cancer, several tumors do not respond similarly to standard approaches. Recent advances in basic research and genomics have improved our understanding of the biologic basis of the tumor development and progression. Tumor profiling allows for more selective therapeutic strategies leading to the identification of biomarkers or indicators of treatment response and to increased clinical efficacy through development of targeted therapies. Several markers have been identified, that are involved in cellular proliferation, interaction with angiogenesis, extracellular matrice adhesion/invasion, apoptosis, cell cycle pathways and DNA repair mechanisms. In this report, molecular profiling of uterine cervix carcinoma were reviewed with a special focus on rationally designed target-based anticancer agents, in order to clarify and to summary the present state of art in these particular promising area in cervix cancer management.

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p73 Protein Expression Correlates With Radiation-Induced Apoptosis in the Lack of p53 Response to Radiation Therapy for Cervical Cancer

Cited by 19 publications

References 34 publications

Transcriptome analysis of glioma cells for the dynamic response to γ-irradiation and dual regulation of apoptosis genes: a new insight into radiotherapy for glioblastomas

Transcriptome analysis of glioma cells for the dynamic response to γ-irradiation and dual regulation of apoptosis genes: a new insight into radiotherapy for glioblastomas

Genome-Wide Expression Analysis Identifies a Modulator of Ionizing Radiation-Induced p53-Independent Apoptosis in Drosophila melanogaster

Molecular profiling of uterine cervix carcinoma: an overview with a special focus on rationally designed target-based anticancer agents

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