PO.CH01.07 · 化学
SR-B1基因变异体、抑制剂以及葡萄糖对乳腺癌IC50的影响
SR-B1 gene variants, inhibitors and the effect of glucose on IC50s in breast cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：已观察到与祖源相关的遗传变异通过遗传性基因变异及其与生活方式和环境的相互作用影响某些癌症和糖尿病的风险。2型糖尿病一直被认为是乳腺癌的一个风险因素，因此提示代谢可能驱动癌症进展。逆向胆固醇转运体和膜受体清道夫受体B1（SR-B1）参与胰岛素抵抗和脂质代谢，本研究将其及其祖源富集变异体作为一个新靶点在乳腺癌中进行评估。
方法：本研究采用三阴性乳腺癌细胞系MDA.MB 231和MDA.MB 468。使用TaqMan SNP基因分型实验对SR-B1错义SNP变异体rs2293440进行SNP基因分型以确定每种细胞系的基因型。细胞在葡萄糖水平不同的培养基中培养，分别为5.5 mM、17.5 mM和25 mM，代表血糖水平指标HbA1C。然后用不同浓度的SR-B1抑制剂药物脂质转运阻断剂1（BLT-1）处理细胞，共48小时。48小时后，使用细胞存活率实验测定每种细胞系在上述条件下的存活百分比。
结果：SNP基因分型结果表明MDA.MB 231含有野生型等位基因，而MDA.MB 468含有变异体等位基因。细胞存活率实验结果显示，在培养基葡萄糖浓度为5.5 mM时，两种细胞系对BLT-1的敏感性分别增加了3倍（MDA.MB 231）和5倍（468），这一点也由IC50值所证实。两种细胞系在较高的培养基葡萄糖浓度17.5和25 mM时均表现出对BLT-1的耐药性，其IC50值增加高达5倍。此外，与MDA.MB 231相比，MDA.MB 468在5.5 mM和17.5 mM培养基葡萄糖浓度下对BLT-1均表现出近2倍的更高敏感性。
结论：这些结果表明血糖水平与癌症中的药物敏感性或药物反应之间存在相关性。此外，我们的结果提示，癌症中对代谢抑制剂药物的反应和葡萄糖代谢也可能受到个体的祖源和遗传变异的影响。
查看英文原文 English abstract
Background: Ancestry-related genetic variations have been observed to influence the risk of certain cancers and diabetes through inherited genetic variations and their interaction with lifestyle and environment. Type 2 diabetes has been considered a risk factor for breast cancer, thus suggesting metabolism may drive cancer progression. The reverse cholesterol transporter and membrane receptor Scavenger receptor B1 (SR-B1), which is involved in insulin resistance and lipid metabolism, with its ancestry enriched variants, is evaluated in breast cancer as a novel target.
Methods: The triple negative breast cancer cell lines MDA.MB 231 and MDA.MB 468 were employed for this study. SNP genotyping to determine the genotype of each cell line was performed using the TaqMan SNP Genotyping assays for the SR-B1 missense SNP variant rs2293440. Cells were grown in media with varying glucose levels of 5.5 mM, 17.5 mM and 25 mM, representative of the blood glucose level indicator HbA1C. The cells were then treated with different concentrations of the SR-B1 inhibitor drug, Block lipid transport 1 (BLT-1), for total of 48 hours. After 48 hours, cell survivability assay was used to determine percent survival for each cell line under the conditions mentioned.
Results: The SNP genotyping results indicated that MDA.MB 231 contained the wild-type allele while MDA.MB 468 contained the variant allele. Results of the cell survivability assay showed that sensitivity of both the cell lines to BLT-1 was increased by 3-fold and 5-fold at 5.5 mM glucose concentration in media for MDA.MB 231 and 468 respectively, as was confirmed by the IC50 values. Both cell lines displayed resistance to BLT-1 at the higher media glucose concentrations of 17.5 and 25 mM with their IC50 values exhibiting up to a 5-fold increase. Further, MDA.MB 468 displayed almost 2-fold higher sensitivity to BLT-1 at both 5.5 mM and 17.5 mM media glucose concentration in comparison to MDA.MB 231.
Conclusions: These results indicate that there is a correlation between the blood glucose levels and the drug sensitivity or drug response in cancer. Further, our results suggest that the response to metabolism inhibitor drugs in cancer and glucose metabolism may also be impacted by the ancestry and genetic variation of an individual.
利益披露 Disclosure
N. Bhattacharya, None..
S. Aramgam, None.