scholarly journals Characterisation of an Isogenic Model of Cisplatin Resistance in Oesophageal Adenocarcinoma Cells

2019 ◽  
Vol 12 (1) ◽  
pp. 33 ◽  
Author(s):  
Amy Buckley ◽  
Becky Bibby ◽  
Margaret Dunne ◽  
Susan Kennedy ◽  
Maria Davern ◽  
...  

Cisplatin (cis-diamminedichloroplatinum) is widely used for the treatment of solid malignancies; however, the development of chemoresistance hinders the success of this chemotherapeutic in the clinic. This study provides novel insights into the molecular and phenotypic changes in an isogenic oesophageal adenocarcinoma (OAC) model of acquired cisplatin resistance. Key differences that could be targeted to overcome cisplatin resistance are highlighted. We characterise the differences in treatment sensitivity, gene expression, inflammatory protein secretions, and metabolic rate in an isogenic cell culture model of acquired cisplatin resistance in OAC. Cisplatin-resistant cells (OE33 Cis R) were significantly more sensitive to other cytotoxic modalities, such as 2 Gy radiation (p = 0.0055) and 5-fluorouracil (5-FU) (p = 0.0032) treatment than parental cisplatin-sensitive cells (OE33 Cis P). Gene expression profiling identified differences at the gene level between cisplatin-sensitive and cisplatin-resistant cells, uncovering 692 genes that were significantly altered between OE33 Cis R cells and OE33 Cis P cells. OAC is an inflammatory-driven cancer, and inflammatory secretome profiling identified 18 proteins secreted at significantly altered levels in OE33 Cis R cells compared to OE33 Cis P cells. IL-7 was the only cytokine to be secreted at a significantly higher levels from OE33 Cis R cells compared to OE33 Cis P cells. Additionally, we profiled the metabolic phenotype of OE33 Cis P and OE33 Cis R cells under normoxic and hypoxic conditions. The oxygen consumption rate, as a measure of oxidative phosphorylation, is significantly higher in OE33 Cis R cells under normoxic conditions. In contrast, under hypoxic conditions of 0.5% O2, the oxygen consumption rate is significantly lower in OE33 Cis R cells than OE33 Cis P cells. This study provides novel insights into the molecular and phenotypic changes in an isogenic OAC model of acquired cisplatin resistance, and highlights therapeutic targets to overcome cisplatin resistance in OAC.

Author(s):  
Grażyna Mazurkiewicz-Boroń ◽  
Teresa Bednarz ◽  
Elżbieta Wilk-Woźniak

Microbial efficiency in a meromictic reservoirIndices of microbial efficiency (expressed as oxygen consumption and carbon dioxide release) were determined in the water column of the meromictic Piaseczno Reservoir (in an opencast sulphur mine), which is rich in sulphur compounds. Phytoplankton abundances were low in both the mixolimnion (up to 15 m depth) and monimolimnion (below 15 m depth). In summer and winter, carbon dioxide release was 3-fold and 5-fold higher, respectively, in the monimolimnion than in the mixolimnion. Laboratory enrichments of the sulphur substrate of the water resulted in a decrease in oxygen consumption rate of by about 42% in mixolimnion samples, and in the carbon dioxide release rate by about 69% in monimolimnion samples. Water temperature, pH and bivalent ion contents were of major importance in shaping the microbial metabolic efficiency in the mixolimnion, whilst in the monimolimnion these relationships were not evident.


2020 ◽  
Vol 20 (12) ◽  
pp. 1487-1496 ◽  
Author(s):  
Midori Murakami ◽  
Hiroto Izumi ◽  
Tomoko Kurita ◽  
Chiho Koi ◽  
Yasuo Morimoto ◽  
...  

Background: Cisplatin is an important anticancer agent in cancer chemotherapy, but when resistant cells appear, treatment becomes difficult, and the prognosis is poor. Objective: In this study, we investigated the gene expression profile in cisplatin sensitive and resistant cells, and identified the genes involved in cisplatin resistance. Methods: Comparison of gene expression profiles revealed that UBE2L6 mRNA is highly expressed in resistant cells. To elucidate whether UBE2L6 is involved in the acquisition of cisplatin resistance, UBE2L6- overexpressing cells established from cisplatin-sensitive cells and UBE2L6-silenced cells developed from cisplatin- resistant cells were generated, and the sensitivity of cisplatin was examined. Results: The sensitivity of the UBE2L6-overexpressing cells did not change compared with the control cells, but the UBE2L6-silenced cells were sensitized to cisplatin. To elucidate the mechanism of UBE2L6 in cisplatin resistance, we compared the gene expression profiles of UBE2L6-silenced cells and control cells and found that the level of ABCB6 mRNA involved in cisplatin resistance was decreased. Moreover, ABCB6 promoter activity was partially suppressed in UBE2L6-silenced cells. Conclusion: These results suggest that cisplatin-resistant cells have upregulated UBE2L6 expression and contribute to cisplatin resistance by regulating ABCB6 expression at the transcriptional level. UBE2L6 might be a molecular target that overcomes cisplatin resistance.


2021 ◽  
Vol 22 (9) ◽  
pp. 4366
Author(s):  
Rebecca L. Paszkiewicz ◽  
Richard N. Bergman ◽  
Roberta S. Santos ◽  
Aaron P. Frank ◽  
Orison O. Woolcott ◽  
...  

The authors wish to make the following corrections to this paper [...]


2021 ◽  
Vol 22 (16) ◽  
pp. 8367
Author(s):  
Hien Lau ◽  
Shiri Li ◽  
Nicole Corrales ◽  
Samuel Rodriguez ◽  
Mohammadreza Mohammadi ◽  
...  

Pre-weaned porcine islets (PPIs) represent an unlimited source for islet transplantation but are functionally immature. We previously showed that necrostatin-1 (Nec-1) immediately after islet isolation enhanced the in vitro development of PPIs. Here, we examined the impact of Nec-1 on the in vivo function of PPIs after transplantation in diabetic mice. PPIs were isolated from pancreata of 8–15-day-old, pre-weaned pigs and cultured in media alone, or supplemented with Nec-1 (100 µM) on day 0 or on day 3 of culture (n = 5 for each group). On day 7, islet recovery, viability, oxygen consumption rate, insulin content, cellular composition, insulin secretion capacity, and transplant outcomes were evaluated. While islet viability and oxygen consumption rate remained high throughout 7-day tissue culture, Nec-1 supplementation on day 3 significantly improved islet recovery, insulin content, endocrine composition, GLUT2 expression, differentiation potential, proliferation capacity of endocrine cells, and insulin secretion. Adding Nec-1 on day 3 of tissue culture enhanced the islet recovery, proportion of delta cells, beta-cell differentiation and proliferation, and stimulation index. In vivo, this leads to shorter times to normoglycemia, better glycemic control, and higher circulating insulin. Our findings identify the novel time-dependent effects of Nec-1 supplementation on porcine islet quantity and quality prior to transplantation.


1991 ◽  
Vol 71 (3) ◽  
pp. 1119-1122 ◽  
Author(s):  
R. Kram

People throughout Asia use springy bamboo poles to carry the loads of everyday life. These poles are a very compliant suspension system that allows the load to move along a nearly horizontal path while the person bounces up and down with each step. Could this be an economical way to carry loads inasmuch as no gravitational work has to be done to lift the load repeatedly? To find out, an experiment was conducted in which four male subjects ran at 3.0 m/s on a motorized treadmill with no load and while carrying a load equal to 19% body wt with compliant poles. Oxygen consumption rate, vertical ground reaction force, and the force exerted by the load on the shoulders were measured. Oxygen consumption rate increased by 22%. The same increase has previously been observed when loads are carried with a backpack. Thus compliant poles are not a particularly economical method of load carriage. However, pole suspension systems offer important advantages: they minimize peak shoulder forces and loading rates. In addition, the peak vertical ground reaction force is only slightly increased above unloaded levels when loads are carried with poles.


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