Thyroid hormones inhibit tumor progression and enhance the antitumor activity of lenvatinib in hepatocellular carcinoma via reprogramming glucose metabolism
Abstract Thyroid hormones (THs) dysfunctions have been demonstrated to be associated with the risk of developing different types of cancers. The role of THs in regulating hepatocellular carcinoma (HCC) progression is still controversial. We demonstrated that T3 can inhibit HCC progression by enhanci...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-03-01
|
| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02378-z |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850029931963088896 |
|---|---|
| author | Chun‑Cheng Yang Yu-Chuan Yan Guo‑Qiang Pan Guang-Xiao Meng Xiao Zhang Lun-Jie Yan Zi-Niu Ding Dong-Xu Wang Rui-Zhe Li Guang-Zhen Li Zhao‑Ru Dong Tao Li |
| author_facet | Chun‑Cheng Yang Yu-Chuan Yan Guo‑Qiang Pan Guang-Xiao Meng Xiao Zhang Lun-Jie Yan Zi-Niu Ding Dong-Xu Wang Rui-Zhe Li Guang-Zhen Li Zhao‑Ru Dong Tao Li |
| author_sort | Chun‑Cheng Yang |
| collection | DOAJ |
| description | Abstract Thyroid hormones (THs) dysfunctions have been demonstrated to be associated with the risk of developing different types of cancers. The role of THs in regulating hepatocellular carcinoma (HCC) progression is still controversial. We demonstrated that T3 can inhibit HCC progression by enhancing the expression of THRSP. Mechanistically, T3 can activate tumor suppressor LKB1/AMPK/Raptor signaling as well as oncogenic PI3K/Akt signaling in HCC. Interestingly, T3-induced THRSP can augment the activation of LKB1/AMPK/Raptor signaling, yet inhibit T3-induced PI3K/Akt signaling activation, thereby preventing mTOR-induced nuclear translocation of HIF-1α, and ultimately suppressing ENO2-induced glycolysis and HCC progression. More importantly, the exogenous T3 enhances the antitumor effect of multikinase inhibitor lenvatinib in vitro and in vivo by regulating glycolysis. Our findings reveal the role and mechanism of THs in HCC progression and glucose metabolism and provide new potential therapeutic strategies for HCC treatment and drug resistance reversal. |
| format | Article |
| id | doaj-art-33db49e3ad9e4088a6a473b4d22cedd1 |
| institution | DOAJ |
| issn | 2058-7716 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj-art-33db49e3ad9e4088a6a473b4d22cedd12025-08-20T02:59:23ZengNature Publishing GroupCell Death Discovery2058-77162025-03-0111111310.1038/s41420-025-02378-zThyroid hormones inhibit tumor progression and enhance the antitumor activity of lenvatinib in hepatocellular carcinoma via reprogramming glucose metabolismChun‑Cheng Yang0Yu-Chuan Yan1Guo‑Qiang Pan2Guang-Xiao Meng3Xiao Zhang4Lun-Jie Yan5Zi-Niu Ding6Dong-Xu Wang7Rui-Zhe Li8Guang-Zhen Li9Zhao‑Ru Dong10Tao Li11Department of General Surgery, Qilu Hospital, Shandong UniversityDepartment of General Surgery, Qilu Hospital, Shandong UniversityDepartment of General Surgery, Qilu Hospital, Shandong UniversityDepartment of General Surgery, Qilu Hospital, Shandong UniversityDepartment of General Surgery, Qilu Hospital, Shandong UniversityDepartment of General Surgery, Qilu Hospital, Shandong UniversityDepartment of General Surgery, Qilu Hospital, Shandong UniversityDepartment of General Surgery, Qilu Hospital, Shandong UniversityDepartment of General Surgery, Qilu Hospital, Shandong UniversityDepartment of General Surgery, Qilu Hospital, Shandong UniversityDepartment of General Surgery, Qilu Hospital, Shandong UniversityDepartment of General Surgery, Qilu Hospital, Shandong UniversityAbstract Thyroid hormones (THs) dysfunctions have been demonstrated to be associated with the risk of developing different types of cancers. The role of THs in regulating hepatocellular carcinoma (HCC) progression is still controversial. We demonstrated that T3 can inhibit HCC progression by enhancing the expression of THRSP. Mechanistically, T3 can activate tumor suppressor LKB1/AMPK/Raptor signaling as well as oncogenic PI3K/Akt signaling in HCC. Interestingly, T3-induced THRSP can augment the activation of LKB1/AMPK/Raptor signaling, yet inhibit T3-induced PI3K/Akt signaling activation, thereby preventing mTOR-induced nuclear translocation of HIF-1α, and ultimately suppressing ENO2-induced glycolysis and HCC progression. More importantly, the exogenous T3 enhances the antitumor effect of multikinase inhibitor lenvatinib in vitro and in vivo by regulating glycolysis. Our findings reveal the role and mechanism of THs in HCC progression and glucose metabolism and provide new potential therapeutic strategies for HCC treatment and drug resistance reversal.https://doi.org/10.1038/s41420-025-02378-z |
| spellingShingle | Chun‑Cheng Yang Yu-Chuan Yan Guo‑Qiang Pan Guang-Xiao Meng Xiao Zhang Lun-Jie Yan Zi-Niu Ding Dong-Xu Wang Rui-Zhe Li Guang-Zhen Li Zhao‑Ru Dong Tao Li Thyroid hormones inhibit tumor progression and enhance the antitumor activity of lenvatinib in hepatocellular carcinoma via reprogramming glucose metabolism Cell Death Discovery |
| title | Thyroid hormones inhibit tumor progression and enhance the antitumor activity of lenvatinib in hepatocellular carcinoma via reprogramming glucose metabolism |
| title_full | Thyroid hormones inhibit tumor progression and enhance the antitumor activity of lenvatinib in hepatocellular carcinoma via reprogramming glucose metabolism |
| title_fullStr | Thyroid hormones inhibit tumor progression and enhance the antitumor activity of lenvatinib in hepatocellular carcinoma via reprogramming glucose metabolism |
| title_full_unstemmed | Thyroid hormones inhibit tumor progression and enhance the antitumor activity of lenvatinib in hepatocellular carcinoma via reprogramming glucose metabolism |
| title_short | Thyroid hormones inhibit tumor progression and enhance the antitumor activity of lenvatinib in hepatocellular carcinoma via reprogramming glucose metabolism |
| title_sort | thyroid hormones inhibit tumor progression and enhance the antitumor activity of lenvatinib in hepatocellular carcinoma via reprogramming glucose metabolism |
| url | https://doi.org/10.1038/s41420-025-02378-z |
| work_keys_str_mv | AT chunchengyang thyroidhormonesinhibittumorprogressionandenhancetheantitumoractivityoflenvatinibinhepatocellularcarcinomaviareprogrammingglucosemetabolism AT yuchuanyan thyroidhormonesinhibittumorprogressionandenhancetheantitumoractivityoflenvatinibinhepatocellularcarcinomaviareprogrammingglucosemetabolism AT guoqiangpan thyroidhormonesinhibittumorprogressionandenhancetheantitumoractivityoflenvatinibinhepatocellularcarcinomaviareprogrammingglucosemetabolism AT guangxiaomeng thyroidhormonesinhibittumorprogressionandenhancetheantitumoractivityoflenvatinibinhepatocellularcarcinomaviareprogrammingglucosemetabolism AT xiaozhang thyroidhormonesinhibittumorprogressionandenhancetheantitumoractivityoflenvatinibinhepatocellularcarcinomaviareprogrammingglucosemetabolism AT lunjieyan thyroidhormonesinhibittumorprogressionandenhancetheantitumoractivityoflenvatinibinhepatocellularcarcinomaviareprogrammingglucosemetabolism AT ziniuding thyroidhormonesinhibittumorprogressionandenhancetheantitumoractivityoflenvatinibinhepatocellularcarcinomaviareprogrammingglucosemetabolism AT dongxuwang thyroidhormonesinhibittumorprogressionandenhancetheantitumoractivityoflenvatinibinhepatocellularcarcinomaviareprogrammingglucosemetabolism AT ruizheli thyroidhormonesinhibittumorprogressionandenhancetheantitumoractivityoflenvatinibinhepatocellularcarcinomaviareprogrammingglucosemetabolism AT guangzhenli thyroidhormonesinhibittumorprogressionandenhancetheantitumoractivityoflenvatinibinhepatocellularcarcinomaviareprogrammingglucosemetabolism AT zhaorudong thyroidhormonesinhibittumorprogressionandenhancetheantitumoractivityoflenvatinibinhepatocellularcarcinomaviareprogrammingglucosemetabolism AT taoli thyroidhormonesinhibittumorprogressionandenhancetheantitumoractivityoflenvatinibinhepatocellularcarcinomaviareprogrammingglucosemetabolism |