...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Journal of cellular physiology. >L-lactic acidosis confers insensitivity to PKC inhibitors by competing for uptake via monocarboxylate transporters
【24h】

L-lactic acidosis confers insensitivity to PKC inhibitors by competing for uptake via monocarboxylate transporters

机译：PKC L-lactic酸中毒授予不敏感争取通过吸收抑制剂monocarboxylate转运蛋白

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相关主题

摘要

Targeting protein kinase C (PKC) family was found to repress the migration and resistance of non-small cell lung cancer cells to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, none of the PKC inhibitors has been approved for anticancer therapy yet due to the limited efficacy in clinical trials, and the underlying mechanisms remain unclear. L-lactic acidosis, a common condition comprising high L-lactate concentration and acidic pH in the tumor micro-environment, has been known to induce tumor metastasis and drug resistance. In this study, L-lactic acid was found to reverse the inhibitory effects of pan-PKC inhibitors GO6983 on PKC activity, cell migration, and EGFR-TKI resistance, but these effects were not affected by the modulators of lactate receptor GPR81. Interestingly, blockade of lactate transporters, monocarboxylate transporter-1 and -4 (MCT1 and MCT4), attenuated the intracellular level of GO6983, and its inhibitory effect on PKC activity, suggesting that lactic acid promotes the resistance to PKC inhibitors by competing for the uptake through these transporters rather than by activating its receptor, GPR81. Our findings explain the underlying mechanisms of the limited response of PKC inhibitors in clinical trials.
机译：目标蛋白激酶C (PKC)的家庭镇压的迁移和阻力非小细胞肺癌细胞表皮生长因子受体(EGFR)酪氨酸激酶抑制剂(TKIs)。抑制剂已被批准用于抗癌治疗由于有限的功效临床试验,和底层机制尚不清楚。包括高L-lactate浓度条件在肿瘤微环境和酸性pH值众所周知,诱发肿瘤转移和药物阻力。发现反向的抑制效应pan-PKC抑制剂GO6983 PKC活性,细胞移民和EGFR-TKI阻力,但这些效果没有影响的调节器乳酸受体GPR81。乳酸转运蛋白,monocarboxylatetransporter-1和4 (MCT1和MCT4),减毒胞内的GO6983水平,它的PKC活性的抑制作用,表明乳酸促进PKC的阻力抑制剂通过竞争吸收这些转运蛋白,而不是通过激活它受体,GPR81。有限的反应的潜在机制PKC抑制剂在临床试验中。

著录项

获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号