Scholarlink

Background <p>Cancer-associated fibroblasts (CAFs) have been identified to drive chemotherapy resistance in triple-negative breast cancer (TNBC). This study evaluated the functions of CAFs-mediated suppressive ferroptosis in doxorubicin (DOX) resistance in TNBC and its detailed molecular mechanisms.</p> Methods <p>TNBC cell lines were co-cultured with CAFs isolated from DOX-sensitive (CAF/S) or DOX-resistant (CAF/R) breast cancer tissues. Cell viability and death were assessed by cell counting Kit-8 (CCK-8) and propidium iodide (PI) staining. Ferroptosis was evaluated by detection of Fe<sup>2+</sup>, malondialdehyde (MDA), glutathione (GSH), and lipid reactive oxygen species (ROS) levels. Histone lactylation was determined by lactate production, pan-Kla and H3K18la expression. Molecular mechanism was determined by chromatin immunoprecipitation (ChIP) and dual luciferase reporter system. Molecule and protein expression was detected by quantitative Real-Time PCR (RT-qPCR), Western blotting, immunofluorescence and immunohistochemical staining. TNBC cells were injected into the mammary fat pad of nude mice to investigate DOX sensitivity in vivo.</p> Results <p>CAFs-derived lactate repressed ferroptosis to confer resistance of TNBC cells to DOX. Moreover, zinc finger protein 64 (ZFP64) expression was elevated in DOX-resistant TNBC and was associated with high histone lactylation level. CAFs facilitated histone lactylation to enhance ZFP64 expression, which triggered ferroptosis inhibition and DOX resistance. In addition, ZFP64 bound to the promoters of GTP cyclohydrolase-1 (GCH1) and ferritin heavy chain 1 (FTH1), thereby promoting their expression. Rescue experiments indicated that ZFP64 silencing-induced ferroptosis and high sensitivity of TNBC cells to DOX could be counteracted by GCH1 or FTH1 overexpression.</p> Conclusion <p>CAFs acted as a ferroptosis inhibitor to cause DOX resistance of TNBC via histone lactylation-mediated ZFP64 up-regulation and subsequent promotion of GCH1-induced lipid peroxidation inhibition and FTH1-induced intracellular Fe<sup>2+</sup> consumption.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Cancer-associated fibroblasts promote doxorubicin resistance in triple-negative breast cancer through enhancing ZFP64 histone lactylation to regulate ferroptosis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年2月28日

查看全文
  • KeJing Zhang,
  • Lei Guo,
  • Xin Li,
  • Yu Hu,
  • Na Luo

摘要

Background

Cancer-associated fibroblasts (CAFs) have been identified to drive chemotherapy resistance in triple-negative breast cancer (TNBC). This study evaluated the functions of CAFs-mediated suppressive ferroptosis in doxorubicin (DOX) resistance in TNBC and its detailed molecular mechanisms.

Methods

TNBC cell lines were co-cultured with CAFs isolated from DOX-sensitive (CAF/S) or DOX-resistant (CAF/R) breast cancer tissues. Cell viability and death were assessed by cell counting Kit-8 (CCK-8) and propidium iodide (PI) staining. Ferroptosis was evaluated by detection of Fe2+, malondialdehyde (MDA), glutathione (GSH), and lipid reactive oxygen species (ROS) levels. Histone lactylation was determined by lactate production, pan-Kla and H3K18la expression. Molecular mechanism was determined by chromatin immunoprecipitation (ChIP) and dual luciferase reporter system. Molecule and protein expression was detected by quantitative Real-Time PCR (RT-qPCR), Western blotting, immunofluorescence and immunohistochemical staining. TNBC cells were injected into the mammary fat pad of nude mice to investigate DOX sensitivity in vivo.

Results

CAFs-derived lactate repressed ferroptosis to confer resistance of TNBC cells to DOX. Moreover, zinc finger protein 64 (ZFP64) expression was elevated in DOX-resistant TNBC and was associated with high histone lactylation level. CAFs facilitated histone lactylation to enhance ZFP64 expression, which triggered ferroptosis inhibition and DOX resistance. In addition, ZFP64 bound to the promoters of GTP cyclohydrolase-1 (GCH1) and ferritin heavy chain 1 (FTH1), thereby promoting their expression. Rescue experiments indicated that ZFP64 silencing-induced ferroptosis and high sensitivity of TNBC cells to DOX could be counteracted by GCH1 or FTH1 overexpression.

Conclusion

CAFs acted as a ferroptosis inhibitor to cause DOX resistance of TNBC via histone lactylation-mediated ZFP64 up-regulation and subsequent promotion of GCH1-induced lipid peroxidation inhibition and FTH1-induced intracellular Fe2+ consumption.