The mechanisms underlying cellular drug resistance have been extensively studied, but little is known about its regulation. We have previously reported that activating transcription factor 4 (ATF4) is upregulated in cisplatinresistant cells and plays a role in cisplatin resistance. Here, we find out a novel relationship between the circadian transcription factor Clock and drug resistance. Clock drives the periodical expression of many genes that regulate hormone release, cell division, sleep-awake cycle and tumor growth. We demonstrate that ATF4 is a direct target of Clock, and that Clock is overexpressed in cisplatin-resistant cells. Furthermore, Clock expression significantly correlates with cisplatin sensitivity, and that the downregulation of either Clock or ATF4 confers sensitivity of A549 cells to cisplatin and etoposide. Notably, ATF4-overexpressing cells show multidrug resistance and marked elevation of intracellular glutathione. The microarray study reveals that genes for glutathione metabolism are generally downregulated by the knockdown of ATF4 expression. These results suggest that the Clock and ATF4 transcription system might play an important role in multidrug resistance through glutathione-dependent redox system, and also indicate that physiological potentials of Clock-controlled redox system might be important to better understand the oxidative stress-associated disorders including cancer and systemic chronotherapy.
Background Several lines of evidence have suggested that maintenance of atrial fibrillation (AF) depends on reentrant mechanisms. Maintenance of reentry necessitates a sufficiently short refractory period and/or delayed conduction, and AF has been associated with both alterations. Fibrosis, cellular dysfunction and gap junction protein alterations occur in AF and cause conduction delay. We performed this study to test the hypothesis that gap junction protein overexpression would improve conduction and prevent AF. Methods and Results Thirty Yorkshire swine were randomized into 2 groups (sinus rhythm (SR) and AF), and within each group into 3 subgroups: sham-operated control, gene therapy with adenovirus expressing connexin (Cx) 40 and Cx43 (n=5 per subgroup). All animals had epicardial gene painting; the AF group had burst atrial pacing. All animals underwent terminal study 7 days after gene transfer. SR animals had strong transgene expression but no atrial conduction changes. In AF animals, controls had reduced and lateralized Cx43 expression, and Cx43 gene transfer restored expression and cellular location to SR control levels. In the AF group, both Cx40 and Cx43 gene transfer improved conduction and reduced AF relative to controls. Conclusions Connexin gene therapy preserved atrial conduction and prevented AF.
Cisplatin is one of the most potent and widely used anti-cancer agents in the treatment of various solid tumors. However, the development of resistance to cisplatin is a major obstacle in clinical treatment. Several mechanisms are thought to be involved in cisplatin resistance, including decreased intracellular drug accumulation, increased levels of cellular thiols, increased nucleotide excision-repair activity and decreased mismatch-repair activity. In general, the molecules responsible for each mechanism are upregulated in cisplatin-resistant cells; this indicates that the transcription factors activated in response to cisplatin might play crucial roles in drug resistance. It is known that the tumor-suppressor proteins p53 and p73, and the oncoprotein c-Myc, which function as transcription factors, influence cellular sensitivity to cisplatin. So far, we have identified several transcription factors involved in cisplatin resistance, including Y-box binding protein-1 (YB-1), CCAAT-binding transcription factor 2 (CTF2), activating transcription factor 4 (ATF4), zinc-finger factor 143 (ZNF143) and mitochondrial transcription factor A (mtTFA). Two of these-YB-1 and ZNF143-lack the high-mobility group (HMG) domain and can bind preferentially to cisplatin-modified DNA in addition to HMG domain proteins or DNA repair proteins, indicating that these transcription factors may also participate in DNA repair. In this review, we summarize the mechanisms of cisplatin resistance and focus on transcription factors involved in the genomic response to cisplatin.
Epithelial-myoepithelial carcinoma (EMC) of the salivary glands is an uncommon, low-grade malignant tumor. A recent report demonstrates sebaceous differentiation in this tumor even though its significance has never been documented as a precise histologic variant. Six cases of EMC exhibiting sebaceous differentiation (sebaceous EMC) of the parotid gland were analyzed for their clinicopathologic features and immunohistochemical characteristics. In addition, primary salivary sebaceous carcinomas were also examined for comparison. In our series, the incidence of sebaceous EMC was 0.2% among 3012 cases of parotid gland tumors and 14.3% of all EMC cases. The 6 patients comprised 2 men and 4 women, age ranging from 77 to 93 years (mean, 83.7 y). Neither cervical lymph node nor distant organ metastases were found in any cases of sebaceous EMC and no patients died of disease, though local recurrences developed in 1 patient. Conversely, cervical lymph node metastasis was detected in 2 of 3 patients with sebaceous carcinoma, 1 of whom died of disease at 12 months. Histologically, all 6 tumors had an area of sebaceous differentiation admixed with features of bilayered ductal structures typical of EMC. A component of sebaceous differentiation was distributed diffusely in 4 tumors and focally in 2. Cytologic atypia of sebaceous EMCs was lesser than that of sebaceous carcinomas. Immunohistochemically, putative myoepithelial markers such as alpha-smooth muscle actin, calponin, p63, cytokeratin 14, S-100 protein, and vimentin were highly expressed in sebaceous EMC. However, the expression of the latter 4 markers was also observed in primary sebaceous carcinomas, whereas these tumors were all negative for alpha-smooth muscle actin and calponin. Positive immunoreactivity for epithelial membrane antigen, adipophilin, and perilipin confirmed sebaceous differentiation in EMC. These results indicate that sebaceous EMC is a low-grade malignancy, similar to conventional EMC. Our data also suggest that immunohistochemical examination of specific myoepithelial markers is helpful in distinguishing sebaceous EMC from sebaceous carcinoma, which may occasionally be associated with an aggressive clinical course.
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