ReferenceID 3868
Tamoxifen activates Nrf2-dependent SQSTM1 transcription to promote endometrial hyperplasia
Theranostics
Long-term application of Tamoxifen (TAM) is usually recommended for hormone receptor positive breast cancer patients. Unfortunately, TAM will inevitably increase the incidence of endometrial hyperplasia even endometrial
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Record Fields
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- Reference Id
- 3868
- Evidence Id
- 20458
- Core Evidence Id
- 20458
- Source Reference Id
- 1027
- Herb2 Reference Id
- HBREF001751
- Subject Paper Key
- HBIN018930_28638475
- Pubmed Id
- 28638475
- Doi
- 10.7150/thno.19135
- Paper Title
- Tamoxifen activates Nrf2-dependent SQSTM1 transcription to promote endometrial hyperplasia
- Paper Abstract
- Long-term application of Tamoxifen (TAM) is usually recommended for hormone receptor positive breast cancer patients. Unfortunately, TAM will inevitably increase the incidence of endometrial hyperplasia even endometrial cancer. Despite of substantial investigations, no effective approaches to prevent TAM-induced endometrial carcinogenesis have been acknowledged. In this study, we found that inhibition of Nrf2 could be valuable to prevent TAM-induced endometrial hyperplasia. Upon TAM treatment, the mRNA and protein expression of autophagy adaptor SQSTM1 was specifically increased in endometrial cells but not breast cancer cells. Knocking-down of SQSTM1 expression retarded TAM-promoted growth of endometrial cancer cells. TAM stimulated SQSTM1 transcription specifically in endometrial cells by enhancing phosphorylation and nuclear translocation of Nrf2. Indeed, the expression of Nrf2 and SQSTM1 were positively correlated in primary endometrial tissues. In rats with TAM-induced endometrial hyperplasia, both Nrf2 and SQSTM1 expression were increased. Nrf2 inhibitor brusatol effectively attenuated TAM-induced SQSTM1 upregulation and endometrial hyperplasia. The kinase of Nrf2, PRKCD, was activated by TAM. Once PRKCD was depleted, TAM failed to promote Nrf2 phosphorylation and SQSTM1 expression. In summary, TAM stimulated Nrf2-dependent SQSTM1 transcription to promote endometrial hyperplasia by activating PRKCD. Therefore, blocking PRKCD-Nrf2-SQSTM1 signaling could be useful to prevent TAM-induced endometrial hyperplasia.
- Journal
- Theranostics
- Publish Year
- 2017
- Experiment Subject
- rat
- Experiment Type
- Animal Experiment
- Phenotype Related
- Paper Title Cn
- Paper Title En
- Tamoxifen activates Nrf2-dependent SQSTM1 transcription to promote endometrial hyperplasia
- Bilingual Status
- semi_complete