Purpose: Dexamethasone (Dex), a glucocorticoid (GC), is used as a pretreatment drug in cancer patients undergoing chemotherapy. Dex functions by binding to the glucocorticoid receptor (GR) to prevent allergic reactions and severe chemotherapeutic side effects such as nausea and vomiting. However, the mechanisms by which Dex causes chemoresistance remain unknown.
Methods: We used docetaxel and cisplatin to treat triple-negative breast cancer (TNBC) cells with or without Dex and assessed cell proliferation using a sulforhodamine B colorimetric (SRB) assay. Additionally, Western blotting was employed to measure Kruppel-like factor 5 (KLF5), GR and several apoptosis-related proteins. To determine how the GR regulates KLF5, we used qRT-PCR, luciferase reporter assays and ChIP assays. Finally, we detected the involvement of Dex in TNBC chemotherapeutic resistance using HCC1806 xenograft model in vivo.
Results: In this study, we demonstrated that Dex induces docetaxel and cisplatin resistance in TNBC cells in vitro and in vivo. Dex up-regulates pro-survival transcription factor KLF5 expression at both mRNA and protein levels dependent on GR. Importantly, Dex failed to promote cancer cell survival and tumor growth when KLF5 induction was blocked.
Conclusions: We conclude that KLF5 is a Dex-induced gene that contributes to Dex-mediated drug chemoresistance, providing a potential novel target for TNBC treatment.
[1]Kunming Med Univ, Affiliated Hosp 1, Inst Gastroenterol, Dept Gastrointestinal & Hernia Surg, Kunming 650032, Yunnan, Peoples R China.
[2]Chinese Acad Sci & Yunnan Prov, Key Lab Anim Models & Human Dis Mech, Kunming Inst Zool, Kunming 650223, Yunnan, Peoples R China.
[3]Kunming Digest Dis Treatment Engn Technol Ctr, Kunming 650032, Yunnan, Peoples R China.
[4]Kunming Med Univ, Yunnan Tumor Hosp, Dept Oncol, Affiliated Hosp 3, Kunming 650118, Yunnan, Peoples R China.
[5]Kunming Med Univ, Yunnan Tumor Hosp, Dept Breast Surg, Affiliated Hosp 3, Kunming 650118, Yunnan, Peoples R China.
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