ABSTRACT
Objective To study the effects of internal exposure of 18F-FDG (18F-2-deoxy-2-fiuoroD-glucose) on the protein expressions of P53,XIAP (X-linked inhibitors of apoptosis protein) and GADD (growth arrest and DNA damage)45 in Lewis lung carcinoma,and to explore the possibility of applying 18F-FDG as a radiotherapy drug in vivo.Methods Lewis lung cancer transplanted tumor models were established via subcutaneous injection of 0.2 ml of 2 × 107/ml Lewis lung carcinoma cells at left hind limbs of 48 C57BL/6 mice that were randomly divided into high dose group,low dose group and control group with 16 mice each.After 7 d of cancer cell inoculation,18.5 × 107 Bq and 9.25 × 107 Bq of 18F-FDG in 0.2 ml saline or equal volume of physiological saline was intraperitoneally injected into three group mice,respectively.22 d post inoculation,the protein expressions of P53,XIAP and GADD45 were immuohistochemically detected by using SP approach.Results There was significant difference among the protein expressions in each group (x2 =8.30,16.02,7.68,P ＜0.05).The mean integral optic density of protein expression increased from 0.089 ± 0.033 in control group to 0.315 ± 0.028 in high dose group for P53,and from 0.126 ± 0.023 to 0.383 ±-0.035 for GADD45,but it decreased from 0.422 ± 0.034 to 0.149 ± 0.055 for XIAP.There was significantly difference of these protein expressions in each group (P53:F=5.26,P＜0.05;XIAP:F=4.29,P ＜0.05;GADD45:F=5.98,P ＜0.05).Conclusions 18F-FDG can up-regulate the expressions of P53 and GADD45 proteins and down-regulate the expression of XIAP protein in tumor cells,and it inhibits tumor growth by promoting cell apoptosis in the Lewis lung carcinoma tissue with a P53-dependent manner.
ABSTRACT
Chromatin structure has a crucial role in a diversity of physiological processes, including development, differentiation and stress responses, via regulation of transcription, DNA replication and DNA damage repair. Histone deacetylase (HDAC) inhibitors regulate chromatin structure and activate the DNA damage checkpoint pathway involving Ataxia-telangiectasia mutated (ATM). Herein, we investigated the impact of histone acetylation/deacetylation modification on the ATM-mediated transcriptional modulation to provide a better understanding of the transcriptional function of ATM. The prototype HDAC inhibitor trichostain A (TSA) reprograms expression of the myeloid cell leukemia-1 (MCL1) and Gadd45alpha genes via the ATM-mediated signal pathway. Transcription of MCL1 and Gadd45alpha is enhanced following TSA treatment in ATM+ cells, but not in isogenic ATM- or kinase-dead ATM expressing cells, in the ATM-activated E2F1 or BRCA1-dependent manner, respectively. These findings suggest that ATM and its kinase activity are essential for the TSA-induced regulation of gene expression. In summary, ATM controls the transcriptional upregulation of MCL1 and Gadd45alpha through the activation of the ATM-mediated signal pathway in response to HDAC inhibition. These findings are important in helping to design combinatory treatment schedules for anticancer radio- or chemo-therapy with HDAC inhibitors.