Academic Journal
Cystathionine-γ-lyase contributes to tamoxifen resistance, and the compound I194496 alleviates this effect by inhibiting the PPARγ/ACSL1/STAT3 signalling pathway in oestrogen receptor-positive breast cancer
| Title: | Cystathionine-γ-lyase contributes to tamoxifen resistance, and the compound I194496 alleviates this effect by inhibiting the PPARγ/ACSL1/STAT3 signalling pathway in oestrogen receptor-positive breast cancer |
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| Authors: | Han Fu, Xue Han, Wenqing Guo, Xuening Zhao, Chunxue Yu, Wei Zhao, Shasha Feng, Jian Wang, Zhenshuai Zhang, Kaijian Lei, Ming Li, Tianxiao Wang |
| Source: | Scientific Reports, Vol 14, Iss 1, Pp 1-14 (2024) |
| Publisher Information: | Nature Portfolio, 2024. |
| Publication Year: | 2024 |
| Collection: | LCC:Medicine LCC:Science |
| Subject Terms: | Cystathionine-γ-lyase (CSE), TAM, Resistance, CSE inhibitor, Breast cancer, Medicine, Science |
| More Details: | Abstract Tamoxifen (TAM) resistance is a major challenge in treating oestrogen receptor-positive (ER+) breast cancers. It is possible that the H2S synthase cystathionine-γ-lyase (CSE), which has been previously shown to promote tumour growth and metastasis in other cancer cells, is involved in this resistance. Therefore, we investigated CSE's role and potential mechanisms in TAM-resistant breast cancer cells. First, we examined the effect of CSE expression on TAM sensitivity and resistance in MCF7 (breast cancer) cells. The findings revealed that CSE was directly associated with TAM sensitivity and involved in TAM resistance in ER+ breast cancer cells, indicating that it may be useful as a biomarker. Next, we wanted to determine the molecular mechanism of CSE's role in TAM resistance. Using cell migration, co-immunoprecipitation, western blotting, and cell viability assays, we determined that the CSE/H2S system can affect the expression of PPARγ by promoting the sulfhydrylation of PPARγ, which regulates the transcriptional activity of ACSL1. ACSL1, in turn, influences STAT3 activation by affecting the phosphorylation, palmitoylation and dimerization of STAT3, ultimately leading to the development of TAM resistance in breast cancer. Finally, we examined the effect of CSE inhibitors on reducing drug resistance to determine whether CSE may be used as a biomarker of TAM resistance. We observed that the novel CSE inhibitor I194496 can reverse TAM resistance in TAM-resistant breast cancer via targeting the PPARγ/ACSL1/STAT3 signalling pathway. Overall, our data indicate that CSE may serve as a biomarker of TAM resistance and that the CSE inhibitor I194496 is a promising candidate for combating TAM resistance. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 2045-2322 |
| Relation: | https://doaj.org/toc/2045-2322 |
| DOI: | 10.1038/s41598-024-71962-7 |
| Access URL: | https://doaj.org/article/fe8ba047515f4f4790a552ca075c91b0 |
| Accession Number: | edsdoj.fe8ba047515f4f4790a552ca075c91b0 |
| Database: | Directory of Open Access Journals |
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| ISSN: | 20452322 |
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| DOI: | 10.1038/s41598-024-71962-7 |
| Published in: | Scientific Reports |
| Language: | English |