Saikosaponin D reverses epinephrine- and norepinephrine-induced gemcitabine resistance in intrahepatic cholangiocarcinoma by downregulating ADRB2/glycolysis signaling.
Saikosaponin D reverses epinephrine- and norepinephrine-induced gemcitabine resistance in intrahepatic cholangiocarcinoma by downregulating ADRB2/glycolysis signaling.
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柴胡皂苷 D 通过下调 ADRB2/糖酵解信号传导逆转肝内胆管癌中肾上腺素和去甲肾上腺素诱导的吉西他滨耐药性
DOI：
10.3724/abbs.2023040
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发表时间：
2023-07-25
影响因子：
3.7
通讯作者：
Jin S
中科院分区：
文献类型：
--
作者：
He H;Guo J;Hu Y;Zhang H;Li X;Zhang J;Jin S
肝内胆管细胞癌（iCCA）是一种高度致命的恶性肿瘤，其发病率和死亡率在全球范围内迅速增加。目前，以吉西他滨为基础的全身化疗是临床主要的治疗方案，但疗效不佳，其作用机制尚未阐明。在这项研究中，我们使用海马胞外通量分析仪来测量糖酵解能力（胞外酸化率，ECAR）和耗氧率（OCR）。检测葡萄糖摄取或乳酸含量，并分析柴胡皂苷D（一种来自柴胡（一种用于疏肝和缓解抑郁的传统中药）的活性化合物）对去甲肾上腺素刺激的iCCA细胞中吉西他滨细胞毒性的影响。我们发现肾上腺素能信号在慢性应激诱导的iCCA治疗抵抗中起着重要作用。去甲肾上腺素（NE）和肾上腺素（E）可增强iCCA细胞的增殖，并通过激活β2-肾上腺素能受体（ADRB 2）干扰对吉西他滨的反应。此外，我们发现NE上调几个药物外排相关基因（如ABCG 2和MDR 1）的表达，并促进iCCA细胞的糖酵解。此外，柴胡皂苷D通过下调ADRB 2水平来逆转iCCA细胞对吉西他滨的不良反应。此外，柴胡皂苷D通过调节MDR 1、ABCG 2、HK 2和GLUT 1的表达来抑制iCCA细胞中的药物外排和糖酵解。总的来说，柴胡皂苷D通过抑制ADRB 2信号传导控制葡萄糖代谢和药物外排来增强吉西他滨的抗肿瘤作用。因此，柴胡皂苷D和吉西他滨的组合可能是治疗iCCA的潜在治疗策略。
Intrahepatic cholangiocarcinoma (iCCA) is a highly fatal malignancy with rapidly increasing incidence and mortality worldwide. Currently, gemcitabine-based systemic chemotherapy is the main clinical therapeutic regimen; however, its efficacy is poor, and its mechanism has not been elucidated. In this study, we use a Seahorse Extracellular Flux analyser to measure glycolysis capacity (extracellular acidification rate, ECAR) and oxygen consumption rate (OCR). The glucose uptake or lactic acid content is detected, and the effects of saikosaponin D, an active compound derived from Bupleuri Radix (a traditional Chinese medicine for soothing the liver and relieving depression), on gemcitabine cytotoxicity in norepinephrine-stimulated iCCA cells are analysed. We find that adrenergic signaling plays a fundamental role in chronic stress-induced therapeutic resistance in iCCA. Norepinephrine (NE) and epinephrine (E) enhance the proliferation of iCCA cells and interfere with the response to gemcitabine through activation of the β2-adrenergic receptor (ADRB2). Furthermore, we find that NE upregulates the expressions of several drug efflux-related genes (such as ABCG2 and MDR1) and promotes glycolysis in iCCA cells. In addition, saikosaponin D reverses the poor response of iCCA cells to gemcitabine by downregulating ADRB2 level. Furthermore, saikosaponin D inhibits drug efflux and glycolysis in iCCA cells by regulating the expressions of MDR1, ABCG2, HK2, and GLUT1. Collectively, saikosaponin D enhances the antitumor effect of gemcitabine by controlling glucose metabolism and drug efflux by inhibiting the ADRB2 signaling. Therefore, the combination of saikosaponin D and gemcitabine may be a potential therapeutic strategy for the treatment of iCCA.
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影响因子：
5.6
作者：
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通讯作者：
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影响因子：
13.5
作者：
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