Scholarlink

Background <p>Triple negative breast cancer (TNBC) represents the most malignant subtype of breast cancer, with heightened invasiveness, frequent recurrence and poor prognosis. Deciphering the molecular mechanisms underlying TNBC pathogenesis and drug resistance is critical for developing precision therapeutics.</p> Methods <p>Through deep-coverage phosphoproteomic profiling of trace clinical specimens across breast cancer subtypes, we identified phosphorylation at serine 39 (S39) on aldolase A (ALDOA) as a TNBC-specific event. Tissue microarray (TMA) analysis, functional assays, ubiquitination and proteasomal degradation assays, glucose metabolism measurements, TurboID IP–MS, and co-immunoprecipitation (Co-IP) were used to define the functional role of ALDOA S39 phosphorylation and its regulatory interactions with TRIM25 and MINK1. To establish translational relevance, we employed multiple preclinical models, including cell line-derived xenografts, patient-derived organoids, and patient-derived orthotopic xenografts to evaluate therapeutic targeting of the MINK1–ALDOA axis.</p> Results <p>Phosphorylation of ALDOA at serine 39 was identified as a TNBC‑associated phosphorylation event. This phosphorylation attenuated TRIM25-mediated ubiquitination, thereby impairing proteasomal degradation and stabilizing ALDOA protein. Stabilized ALDOA enhanced glycolysis, as indicated by increased glucose uptake, lactate secretion, and ATP production, ultimately driving TNBC progression. We further identified MINK1 as the upstream kinase responsible for ALDOA-S39 phosphorylation. Pharmacological inhibition of MINK1 with the selective small-molecule inhibitor KY-05009 effectively destabilized ALDOA, suppressed glycolysis, and attenuated tumor growth and metastasis across multiple preclinical models.</p> Conclusions <p>Our findings reveal the MINK1–ALDOA axis as a central regulator of glucose metabolic reprogramming and nominate this pathway as a promising therapeutic target for metabolic intervention in TNBC.</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

MINK1 inhibition suppresses triple-negative breast cancer by abrogating ALDOA S39 phosphorylation and reprogramming glucose metabolism

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年8月3日

查看全文
  • Yunwei Shi,
  • Xiujuan Zhang,
  • Tao Zuo,
  • Jinfang Liu,
  • Zhenpeng Zhang,
  • Liying Men,
  • Ruixi Liu,
  • Yi Sun,
  • Sihong Wang,
  • Lei Chang,
  • Deyu Zhang,
  • Juanjuan Li,
  • Qinong Ye,
  • Ping Xu

摘要

Background

Triple negative breast cancer (TNBC) represents the most malignant subtype of breast cancer, with heightened invasiveness, frequent recurrence and poor prognosis. Deciphering the molecular mechanisms underlying TNBC pathogenesis and drug resistance is critical for developing precision therapeutics.

Methods

Through deep-coverage phosphoproteomic profiling of trace clinical specimens across breast cancer subtypes, we identified phosphorylation at serine 39 (S39) on aldolase A (ALDOA) as a TNBC-specific event. Tissue microarray (TMA) analysis, functional assays, ubiquitination and proteasomal degradation assays, glucose metabolism measurements, TurboID IP–MS, and co-immunoprecipitation (Co-IP) were used to define the functional role of ALDOA S39 phosphorylation and its regulatory interactions with TRIM25 and MINK1. To establish translational relevance, we employed multiple preclinical models, including cell line-derived xenografts, patient-derived organoids, and patient-derived orthotopic xenografts to evaluate therapeutic targeting of the MINK1–ALDOA axis.

Results

Phosphorylation of ALDOA at serine 39 was identified as a TNBC‑associated phosphorylation event. This phosphorylation attenuated TRIM25-mediated ubiquitination, thereby impairing proteasomal degradation and stabilizing ALDOA protein. Stabilized ALDOA enhanced glycolysis, as indicated by increased glucose uptake, lactate secretion, and ATP production, ultimately driving TNBC progression. We further identified MINK1 as the upstream kinase responsible for ALDOA-S39 phosphorylation. Pharmacological inhibition of MINK1 with the selective small-molecule inhibitor KY-05009 effectively destabilized ALDOA, suppressed glycolysis, and attenuated tumor growth and metastasis across multiple preclinical models.

Conclusions

Our findings reveal the MINK1–ALDOA axis as a central regulator of glucose metabolic reprogramming and nominate this pathway as a promising therapeutic target for metabolic intervention in TNBC.