RÉSUMÉ
Numerous studies have attempted to develop biological markers for the response to radiation for broad and straightforward application in the field of radiation. Based on a public database, the present study selected several molecules involved in the DNA damage repair response, cell cycle regulation and cytokine signaling as promising candidates for lowdose radiationsensitive markers. The HuT 78 and IM9 cell lines were irradiated in a concentrationdependent manner, and the expression of these molecules was analyzed using western blot analysis. Notably, the activation of ataxia telangiectasia mutated (ATM), checkpoint kinase 2 (CHK2), p53 and H2A histone family member X (H2AX) significantly increased in a concentrationdependent manner, which was also observed in human peripheral blood mononuclear cells. To determine the radioprotective effects of cinobufagin, as an ATM and CHK2 activator, an in vivo model was employed using sublethal and lethal doses in irradiated mice. Treatment with cinobufagin increased the number of bone marrow cells in sublethal irradiated mice, and slightly elongated the survival of lethally irradiated mice, although the difference was not statistically significant. Therefore, KU60019, BML277, pifithrinα, and nutlin3a were evaluated for their ability to modulate radiationinduced cell death. The use of BML277 led to a decrease in radiationinduced pCHK2 and γH2AX levels and mitigated radiationinduced apoptosis. On the whole, the present study provides a novel approach for developing drug candidates based on the profiling of biological radiationsensitive markers. These markers hold promise for predicting radiation exposure and assessing the associated human risk.
Sujet(s)
Protéines mutées dans l'ataxie-télangiectasie , Altération de l'ADN , Rayonnement ionisant , Transduction du signal , Altération de l'ADN/effets des radiations , Altération de l'ADN/effets des médicaments et des substances chimiques , Humains , Animaux , Transduction du signal/effets des médicaments et des substances chimiques , Transduction du signal/effets des radiations , Protéines mutées dans l'ataxie-télangiectasie/métabolisme , Souris , Checkpoint kinase 2/métabolisme , Checkpoint kinase 2/génétique , Histone/métabolisme , Protéine p53 suppresseur de tumeur/métabolisme , Protéine p53 suppresseur de tumeur/génétique , Mâle , Imidazoles/pharmacologie , Radioprotecteurs/pharmacologie , Lignée cellulaire tumorale , Relation dose-effet des rayonnementsRÉSUMÉ
INTRODUCTION: Laryngeal squamous cell carcinoma (LSCC) is the most common histological subtype of laryngeal cancer. The involved molecular mechanisms and suitable therapeutic targets for LSCC still need to be further investigated. Checkpoint kinase 2 (CHK2) participates in several cellular physiology pathways and plays a role in tumor progression. However, the roles of CHK2 in LSCC remain unclear. METHODS: mRNA expression data were obtained from The Cancer Genome Atlas (TCGA) database, and bioinformatic analysis was performed. Western blot and immunohistochemical analyses were conducted to detect protein expression. MTS assays were performed to examine cell growth of LSCC-derived cell lines. RESULTS: In the present study, we found that both active form of CHK2 and total CHK2 protein expressions were up-regulated in LSCC tissues. Positive expression of CHK2 was closely associated with advanced clinical features and poor prognosis. Moreover, potential CHK2-involving bioprocesses and signaling pathways were analyzed. In addition, repressed proliferation of LSCC cells was induced by CHK2 inhibitor. DISCUSSION: Taken together, our findings elucidated that CHK2 may act as an oncogenic factor in LSCC, suggesting a potential target for clinical treatment.