HCAR1/MCT1 regulates tumor ferroptosis through the lactate-mediated AMPK-SCD1 activity and its therapeutic implications
Ferroptosis is a recently discovered form of programed cell death caused by the metabolically regulated lipid peroxidation and holds promise for cancer treatment, but its regulatory mechanisms remain elusive. In this study, we observe that lactate-rich liver cancer cells exhibit enhanced resistance...
| Main Authors: | , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
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2021
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| Online Access: | https://hdl.handle.net/10356/146149 |
| _version_ | 1811681494097199104 |
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| author | Zhao, Youbo Li, Menghuan Yao, Xuemei Fei, Yang Lin, Zhenghong Li, Zhengguo Cai, Kaiyong Zhao, Yanli Luo, Zhong |
| author2 | School of Physical and Mathematical Sciences |
| author_facet | School of Physical and Mathematical Sciences Zhao, Youbo Li, Menghuan Yao, Xuemei Fei, Yang Lin, Zhenghong Li, Zhengguo Cai, Kaiyong Zhao, Yanli Luo, Zhong |
| author_sort | Zhao, Youbo |
| collection | NTU |
| description | Ferroptosis is a recently discovered form of programed cell death caused by the metabolically regulated lipid peroxidation and holds promise for cancer treatment, but its regulatory mechanisms remain elusive. In this study, we observe that lactate-rich liver cancer cells exhibit enhanced resistance to the ferroptotic damage induced by common ferroptosis inducers such as Ras-selective lethal small molecule 3 (RSL3) and Erastin and that the monocarboxylate transporter 1 (MCT1)-mediated lactate uptake could promote ATP production in hepatocellular carcinoma (HCC) cells and deactivate the energy sensor AMP-activated protein kinase (AMPK), leading to the upregulation of sterol regulatory element-binding protein 1 (SREBP1) and the downstream stearoyl-coenzyme A (CoA) desaturase-1 (SCD1) to enhance the production of anti-ferroptosis monounsaturated fatty acids. Additionally, blocking the lactate uptake via hydroxycarboxylic acid receptor 1 (HCAR1)/MCT1 inhibition promotes ferroptosis by activating the AMPK to downregulate SCD1, which may synergize with its acyl-coenzyme A synthetase 4 (ACSL4)-promoting effect to amplify the ferroptotic susceptibility. In vitro and in vivo evidence confirms that lactate regulates the ferroptosis of HCC cells and highlights its translational potential as a therapeutic target for ferroptosis-based tumor treatment. |
| first_indexed | 2024-10-01T03:41:50Z |
| format | Journal Article |
| id | ntu-10356/146149 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T03:41:50Z |
| publishDate | 2021 |
| record_format | dspace |
| spelling | ntu-10356/1461492023-02-28T19:22:11Z HCAR1/MCT1 regulates tumor ferroptosis through the lactate-mediated AMPK-SCD1 activity and its therapeutic implications Zhao, Youbo Li, Menghuan Yao, Xuemei Fei, Yang Lin, Zhenghong Li, Zhengguo Cai, Kaiyong Zhao, Yanli Luo, Zhong School of Physical and Mathematical Sciences Science::Chemistry Lactate Ferroptosis Ferroptosis is a recently discovered form of programed cell death caused by the metabolically regulated lipid peroxidation and holds promise for cancer treatment, but its regulatory mechanisms remain elusive. In this study, we observe that lactate-rich liver cancer cells exhibit enhanced resistance to the ferroptotic damage induced by common ferroptosis inducers such as Ras-selective lethal small molecule 3 (RSL3) and Erastin and that the monocarboxylate transporter 1 (MCT1)-mediated lactate uptake could promote ATP production in hepatocellular carcinoma (HCC) cells and deactivate the energy sensor AMP-activated protein kinase (AMPK), leading to the upregulation of sterol regulatory element-binding protein 1 (SREBP1) and the downstream stearoyl-coenzyme A (CoA) desaturase-1 (SCD1) to enhance the production of anti-ferroptosis monounsaturated fatty acids. Additionally, blocking the lactate uptake via hydroxycarboxylic acid receptor 1 (HCAR1)/MCT1 inhibition promotes ferroptosis by activating the AMPK to downregulate SCD1, which may synergize with its acyl-coenzyme A synthetase 4 (ACSL4)-promoting effect to amplify the ferroptotic susceptibility. In vitro and in vivo evidence confirms that lactate regulates the ferroptosis of HCC cells and highlights its translational potential as a therapeutic target for ferroptosis-based tumor treatment. Published version 2021-01-28T04:17:46Z 2021-01-28T04:17:46Z 2020 Journal Article Zhao, Y., Li, M., Yao, X., Fei, Y., Lin, Z., Li, Z., Cai, K., Zhao, Y. & Luo, Z. (2020). HCAR1/MCT1 regulates tumor ferroptosis through the lactate-mediated AMPK-SCD1 activity and its therapeutic implications. Cell Reports, 33(10). https://dx.doi.org/10.1016/j.celrep.2020.108487 2211-1247 0000-0002-9019-3314 https://hdl.handle.net/10356/146149 10.1016/j.celrep.2020.108487 33296645 2-s2.0-85097481152 10 33 en Cell reports © 2020 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). application/pdf |
| spellingShingle | Science::Chemistry Lactate Ferroptosis Zhao, Youbo Li, Menghuan Yao, Xuemei Fei, Yang Lin, Zhenghong Li, Zhengguo Cai, Kaiyong Zhao, Yanli Luo, Zhong HCAR1/MCT1 regulates tumor ferroptosis through the lactate-mediated AMPK-SCD1 activity and its therapeutic implications |
| title | HCAR1/MCT1 regulates tumor ferroptosis through the lactate-mediated AMPK-SCD1 activity and its therapeutic implications |
| title_full | HCAR1/MCT1 regulates tumor ferroptosis through the lactate-mediated AMPK-SCD1 activity and its therapeutic implications |
| title_fullStr | HCAR1/MCT1 regulates tumor ferroptosis through the lactate-mediated AMPK-SCD1 activity and its therapeutic implications |
| title_full_unstemmed | HCAR1/MCT1 regulates tumor ferroptosis through the lactate-mediated AMPK-SCD1 activity and its therapeutic implications |
| title_short | HCAR1/MCT1 regulates tumor ferroptosis through the lactate-mediated AMPK-SCD1 activity and its therapeutic implications |
| title_sort | hcar1 mct1 regulates tumor ferroptosis through the lactate mediated ampk scd1 activity and its therapeutic implications |
| topic | Science::Chemistry Lactate Ferroptosis |
| url | https://hdl.handle.net/10356/146149 |
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