Saikosaponin D reverses epinephrine- and norepinephrine-induced gemcitabine resistance in intrahepatic cholangiocarcinoma by downregulating ADRB2/glycolysis signaling
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 efficac...
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| Format: | Article |
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China Science Publishing & Media Ltd.
2023-07-01
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| Series: | Acta Biochimica et Biophysica Sinica |
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| Online Access: | https://www.sciengine.com/doi/10.3724/abbs.2023040 |
| _version_ | 1797635901999808512 |
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| author | He Hui Guo Jiaqi Hu Yunxiang Zhang Han Li Xinyang Zhang Jian Jin Shi |
| author_facet | He Hui Guo Jiaqi Hu Yunxiang Zhang Han Li Xinyang Zhang Jian Jin Shi |
| author_sort | He Hui |
| collection | DOAJ |
| description | 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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| issn | 1672-9145 |
| language | English |
| last_indexed | 2024-03-11T12:26:44Z |
| publishDate | 2023-07-01 |
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| series | Acta Biochimica et Biophysica Sinica |
| spelling | doaj.art-6c5364d3579c479e8fc1e59bb4c58a5c2023-11-06T08:30:42ZengChina Science Publishing & Media Ltd.Acta Biochimica et Biophysica Sinica1672-91452023-07-01551404141410.3724/abbs.202304020d259ccSaikosaponin D reverses epinephrine- and norepinephrine-induced gemcitabine resistance in intrahepatic cholangiocarcinoma by downregulating ADRB2/glycolysis signalingHe Hui0Guo Jiaqi1Hu Yunxiang2Zhang Han3Li Xinyang4Zhang Jian5Jin Shi6["Department of Laparoscopic Surgery, the First Affiliated Hospital of Dalian Medical University, Dalian 116000, China"]["Department of Laparoscopic Surgery, the First Affiliated Hospital of Dalian Medical University, Dalian 116000, China"]["Department of Laparoscopic Surgery, the First Affiliated Hospital of Dalian Medical University, Dalian 116000, China"]["Department of Laparoscopic Surgery, the First Affiliated Hospital of Dalian Medical University, Dalian 116000, China"]["Department of Laparoscopic Surgery, the First Affiliated Hospital of Dalian Medical University, Dalian 116000, China"]["Department of Interventional Therapy, the First Affiliated Hospital of Dalian Medical University, Dalian 116000, China"]["Department of Laparoscopic Surgery, the First Affiliated Hospital of Dalian Medical University, Dalian 116000, China"]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.https://www.sciengine.com/doi/10.3724/abbs.2023040saikosaponin Dgemcitabine resistanceintrahepatic cholangiocarcinomaADRB2glycolysis |
| spellingShingle | He Hui Guo Jiaqi Hu Yunxiang Zhang Han Li Xinyang Zhang Jian Jin Shi Saikosaponin D reverses epinephrine- and norepinephrine-induced gemcitabine resistance in intrahepatic cholangiocarcinoma by downregulating ADRB2/glycolysis signaling Acta Biochimica et Biophysica Sinica saikosaponin D gemcitabine resistance intrahepatic cholangiocarcinoma ADRB2 glycolysis |
| title | Saikosaponin D reverses epinephrine- and norepinephrine-induced gemcitabine resistance in intrahepatic cholangiocarcinoma by downregulating ADRB2/glycolysis signaling |
| title_full | Saikosaponin D reverses epinephrine- and norepinephrine-induced gemcitabine resistance in intrahepatic cholangiocarcinoma by downregulating ADRB2/glycolysis signaling |
| title_fullStr | Saikosaponin D reverses epinephrine- and norepinephrine-induced gemcitabine resistance in intrahepatic cholangiocarcinoma by downregulating ADRB2/glycolysis signaling |
| title_full_unstemmed | Saikosaponin D reverses epinephrine- and norepinephrine-induced gemcitabine resistance in intrahepatic cholangiocarcinoma by downregulating ADRB2/glycolysis signaling |
| title_short | Saikosaponin D reverses epinephrine- and norepinephrine-induced gemcitabine resistance in intrahepatic cholangiocarcinoma by downregulating ADRB2/glycolysis signaling |
| title_sort | saikosaponin d reverses epinephrine and norepinephrine induced gemcitabine resistance in intrahepatic cholangiocarcinoma by downregulating adrb2 glycolysis signaling |
| topic | saikosaponin D gemcitabine resistance intrahepatic cholangiocarcinoma ADRB2 glycolysis |
| url | https://www.sciengine.com/doi/10.3724/abbs.2023040 |
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