Wang Hsueh-Chun, Li Yi-Chuan, Hung Mien-Chie
Graduate Institute of Biomedical Sciences, China Medical University Taichung 406040, Taiwan.
Department of Biological Science and Technology, China Medical University Taichung 406040, Taiwan.
Am J Cancer Res. 2025 Mar 15;15(3):1133-1147. doi: 10.62347/LHYO6433. eCollection 2025.
Over 70% of breast cancers are estrogen receptor (ER)-positive, with Tamoxifen (Tam) being a standard treatment. However, around 40% of these cancers develop resistance to Tam, which poses a significant clinical challenge. The ACOD1/itaconate (ITA) axis, a metabolic pathway that produces itaconate, has shown promise in inhibiting the growth of ER-positive breast cancer cells. Nonetheless, it remains unclear how effective ITA is against Tam-resistant breast cancer cells and the underlying mechanisms involved. The current report found that Tam-resistant cells exhibit increased sensitivity to ITA compared to their parental cells and show a synergetic effect in combination treatment with Tam. An unbiased proteomic analysis revealed that upregulating the ERK2 signaling pathway contributes to the sensitivity of ER-positive breast cancer cells to ITA. ITA treatment increases ERK2 phosphorylation at T185/Y187 sites by directly alkylating cysteine 254, leading to ERK2 activation and subsequent cell growth inhibition. These effects were abolished in ITA allylation-resistant cells when a cysteine residue was replaced with serine. Additionally, itaconate-induced ERK2 phosphorylation and activation inhibits the growth of Tam-resistant breast cancer cells, which effect is advanced in phosphorylation-mimic ERK2_T185E-expressing cells but blocked in those expressing non-phosphorylation-mimic ERK2_T185A. Furthermore, activated ERK2 interacts physically with API5 to disrupt API5's localization to the nucleus speckle, where API5 may interact with other molecules critical in regulating cell growth-related genes. Our findings clarify the mechanism through which ITA exerts its effects on tamoxifen-sensitive and resistant breast cancer cells and highlight the potential of itaconate as an alternative treatment strategy against breast cancer.
超过70%的乳腺癌为雌激素受体（ER）阳性，他莫昔芬（Tam）是标准治疗药物。然而，这些癌症中约40%会对Tam产生耐药性，这构成了重大的临床挑战。ACOD1/衣康酸（ITA）轴是一条产生衣康酸的代谢途径，已显示出抑制ER阳性乳腺癌细胞生长的潜力。尽管如此，ITA对Tam耐药乳腺癌细胞的有效性以及所涉及的潜在机制仍不清楚。本报告发现，与亲代细胞相比，Tam耐药细胞对ITA表现出更高的敏感性，并且在与Tam联合治疗时显示出协同效应。一项无偏向性蛋白质组学分析表明，上调ERK2信号通路有助于ER阳性乳腺癌细胞对ITA的敏感性。ITA处理通过直接烷基化半胱氨酸254增加ERK2在T185/Y187位点的磷酸化，导致ERK2激活并随后抑制细胞生长。当半胱氨酸残基被丝氨酸取代时，这些效应在ITA烯丙基化耐药细胞中被消除。此外，衣康酸诱导的ERK2磷酸化和激活抑制了Tam耐药乳腺癌细胞的生长，在表达磷酸化模拟物ERK2_T185E的细胞中这种效应更明显，但在表达非磷酸化模拟物ERK2_T185A的细胞中被阻断。此外，激活的ERK2与API5发生物理相互作用，破坏API5在核斑点的定位，而API5可能在核斑点与其他对调节细胞生长相关基因至关重要的分子相互作用。我们的研究结果阐明了ITA对他莫昔芬敏感和耐药乳腺癌细胞发挥作用的机制，并突出了衣康酸作为乳腺癌替代治疗策略的潜力。
