Profiling and targeting of cellular bioenergetics: inhibition of pancreatic cancer cell proliferation.
Profiling and targeting of cellular bioenergetics: inhibition of pancreatic cancer cell proliferation.
复制标题
DOI：
10.1038/bjc.2014.272
复制
发表时间：
2014-07-08
影响因子：
8.8
通讯作者：
Kalyanaraman, B.
中科院分区：
文献类型：
--
作者：
Cheng, G.;Zielonka, J.;McAllister, D.;Tsai, S.;Dwinell, M. B.;Kalyanaraman, B.
关键词：
靶向线粒体生物能量学和糖酵解途径是抑制肿瘤细胞增殖的有效方法，包括对常规化疗药物具有抗性的肿瘤细胞。在这项研究中，使用海马96孔细胞外通量分析仪，我们映射了两个内在的细胞生物能量参数，耗氧率和质子产生率在六个不同的胰腺癌细胞系，并确定其差异敏感性线粒体和糖酵解抑制剂。糖酵解抑制剂2-脱氧葡萄糖（2-DG）处理不同遗传背景的胰腺癌细胞后，细胞内生物能量参数、ATP耗竭和抗增殖效应（抑制集落形成能力）之间存在着非常密切的关系。糖酵解最多的胰腺癌细胞系对2-DG非常敏感，而糖酵解最少的胰腺癌细胞对2-DG耐药。然而，当与二甲双胍，线粒体呼吸抑制剂和AMP活化蛋白激酶的激活剂，2-DG协同增强ATP消耗和抑制细胞增殖，即使在糖酵解不良，2-DG耐药的胰腺癌细胞系。此外，用常规化疗药物（例如，吉西他滨和多柔比星）或考克斯-2抑制剂塞来昔布使细胞对2-DG处理敏感。细胞生物能量学的详细分析可以为抑制胰腺癌细胞代谢和增殖的治疗策略的设计提供新的见解。
Targeting both mitochondrial bioenergetics and glycolysis pathway is an effective way to inhibit proliferation of tumour cells, including those that are resistant to conventional chemotherapeutics. In this study, using the Seahorse 96-well Extracellular Flux Analyzer, we mapped the two intrinsic cellular bioenergetic parameters, oxygen consumption rate and proton production rate in six different pancreatic cancer cell lines and determined their differential sensitivity to mitochondrial and glycolytic inhibitors. There exists a very close relationship among intracellular bioenergetic parameters, depletion of ATP and anti-proliferative effects (inhibition of colony-forming ability) in pancreatic cancer cells derived from different genetic backgrounds treated with the glycolytic inhibitor, 2-deoxyglucose (2-DG). The most glycolytic pancreatic cancer cell line was exquisitely sensitive to 2-DG, whereas the least glycolytic pancreatic cancer cell was resistant to 2-DG. However, when combined with metformin, inhibitor of mitochondrial respiration and activator of AMP-activated protein kinase, 2-DG synergistically enhanced ATP depletion and inhibited cell proliferation even in poorly glycolytic, 2-DG-resistant pancreatic cancer cell line. Furthermore, treatment with conventional chemotherapeutic drugs (e.g., gemcitabine and doxorubicin) or COX-2 inhibitor, celecoxib, sensitised the cells to 2-DG treatment. Detailed profiling of cellular bioenergetics can provide new insight into the design of therapeutic strategies for inhibiting pancreatic cancer cell metabolism and proliferation.
登录
查看更多内容
影响因子：
2.9
作者：
Deer EL;González-Hernández J;Coursen JD;Shea JE;Ngatia J;Scaife CL;Firpo MA;Mulvihill SJ
通讯作者：
Mulvihill SJ
影响因子：
2.9
作者：
Liu, H;Hu, YP;Lampidis, TJ
通讯作者：
Lampidis, TJ
影响因子：
4.5
作者：
Kung HN;Marks JR;Chi JT
通讯作者：
Chi JT
DOI：
10.1158/1078-0432.ccr-12-0041
发表时间：
2012-08-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Le A;Rajeshkumar NV;Maitra A;Dang CV
通讯作者：
Dang CV
影响因子：
11.2
作者：
Iliopoulos D;Hirsch HA;Struhl K
通讯作者：
Struhl K