PMID- 36293372 OWN - NLM STAT- MEDLINE DCOM- 20221028 LR - 20221030 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 23 IP - 20 DP - 2022 Oct 19 TI - Thyroid Hormone Receptor beta Knockdown Reduces Suppression of Progestins by Activating the mTOR Pathway in Endometrial Cancer Cells. LID - 10.3390/ijms232012517 [doi] LID - 12517 AB - Progestin resistance is a major obstacle to conservative therapy in patients with endometrial cancer (EC) and endometrial atypical hyperplasia (EAH). However, the related inducing factor is yet unclear. In this study, thyroid hormone and its receptor alpha (TRalpha) and beta (TRbeta) of patients were assayed. THRB-silenced RL95-2 and KLE EC cells were cultured to investigate the response of progestins. Transcriptomics and Western blotting were performed to investigate the changes in signaling pathways. We found that THRB, rather than THRA, knockdown promoted the viability and motilities of RL95-2 cells but not KLE cells. The suppressive effect of progestins on cell growth and motility significantly decreased in THRB-silenced RL95-2 cells. Multiple proliferation-related signaling pathways were enriched, and the activities of mammalian targets of rapamycin (mTOR)/4e-binding protein 1 (4EBP1)/eukaryotic translation initiation factor 4G (eIF4G) rather than phosphorylated protein kinase B (Akt) were remarkably boosted. Progestin treatment enhanced the effects, and the augmentation was partially abated on supplementation with T3. In THRB-knockdown KLE cells, the progestins-activated partial signaling pathway expression (either mTOR or eIF4G), and supplementation with T3 did not induce noticeable alterations. The serum levels of triiodothyronine (T3) were significantly lower in patients with EC compared with healthy women. A strong expression of TRbeta was observed in most patients with EC and EAH sensitive to progestin treatment. In contrast, TRalpha positive expression was detected in less than half of the patients sensitive to progestin therapy. In conclusion, THRB knockdown enhanced the viability and motility of type I EC cells and attenuated the suppressive effects of progestins by activating the mTOR-4EBP1/eIF4G pathway. Lower expression of THRB is likely correlated with progesterone resistance. FAU - Ren, Bingtao AU - Ren B AD - School of Pharmacy, Fudan University, Shanghai 200032, China. AD - Lab of Reproductive Pharmacology, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai 200032, China. FAU - Zhou, Jieyun AU - Zhou J AD - Lab of Reproductive Pharmacology, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai 200032, China. FAU - Hu, Yingyi AU - Hu Y AD - School of Pharmacy, Fudan University, Shanghai 200032, China. AD - Lab of Reproductive Pharmacology, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai 200032, China. FAU - Zhong, Ruihua AU - Zhong R AD - Lab of Reproductive Pharmacology, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai 200032, China. FAU - Lv, Qiaoying AU - Lv Q AD - Department of Gynecology, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China. FAU - Xie, Shuwu AU - Xie S AUID- ORCID: 0000-0001-5753-6824 AD - Lab of Reproductive Pharmacology, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai 200032, China. FAU - Li, Guoting AU - Li G AD - Lab of Reproductive Pharmacology, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai 200032, China. FAU - Yang, Bingyi AU - Yang B AD - Department of Gynecology, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China. FAU - Chen, Xiaojun AU - Chen X AD - Department of Gynecology, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China. FAU - Zhu, Yan AU - Zhu Y AUID- ORCID: 0000-0001-5136-7601 AD - Lab of Reproductive Pharmacology, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai 200032, China. LA - eng GR - # CX2022-01/Innovation-oriented Science and Technology Grant from NHC Key Laboratory of Reproduction Regulation/ PT - Journal Article DEP - 20221019 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Progestins) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - 0 (Thyroid Hormone Receptors beta) RN - 0 (Eukaryotic Initiation Factor-4G) RN - 06LU7C9H1V (Triiodothyronine) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) RN - EC 2.7.1.1 (MTOR protein, human) SB - IM MH - Animals MH - Humans MH - Female MH - *Progestins/pharmacology MH - Proto-Oncogene Proteins c-akt MH - Thyroid Hormone Receptors beta MH - Eukaryotic Initiation Factor-4G MH - Triiodothyronine/pharmacology MH - *Endometrial Neoplasms/drug therapy/genetics/metabolism MH - TOR Serine-Threonine Kinases MH - Sirolimus MH - Mammals PMC - PMC9604373 OTO - NOTNLM OT - endometrial cancer OT - mTOR signaling pathway OT - medroxyprogesterone acetate OT - nomegestrol acetate OT - progestin resistance OT - thyroid hormone receptor COIS- The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. EDAT- 2022/10/28 06:00 MHDA- 2022/10/29 06:00 PMCR- 2022/10/19 CRDT- 2022/10/27 01:23 PHST- 2022/08/13 00:00 [received] PHST- 2022/10/10 00:00 [revised] PHST- 2022/10/12 00:00 [accepted] PHST- 2022/10/27 01:23 [entrez] PHST- 2022/10/28 06:00 [pubmed] PHST- 2022/10/29 06:00 [medline] PHST- 2022/10/19 00:00 [pmc-release] AID - ijms232012517 [pii] AID - ijms-23-12517 [pii] AID - 10.3390/ijms232012517 [doi] PST - epublish SO - Int J Mol Sci. 2022 Oct 19;23(20):12517. doi: 10.3390/ijms232012517.