Division of Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstraße 6/IV, Graz, 8010, Austria.
Department of Medicine I, Division of Oncology, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, 1090, Austria.
Cell Commun Signal. 2024 Nov 6;22(1):533. doi: 10.1186/s12964-024-01917-y.
High levels of thyroid hormones are linked to increased risk and advanced stages of breast cancer. Our previous work demonstrated that the biologically active triiodothyronine (T3) facilitates mitochondrial ATP production by upregulating Ca handling proteins, thereby boosting mitochondrial Ca uptake and Krebs cycle activity. In this study, different cell types were utilized to investigate whether T3 activates a Ca-induced signaling pathway to boost cancer cell proliferation. Using live-cell imaging, biochemical assays, and molecular profiling, differences in intracellular signaling among MCF7 and MDA-MB-468 breast cancer cells, non-cancerous breast cells hTERT-HME1, and PC3 prostate carcinoma cells, previously found to be insensitive to thyroid hormones in terms of proliferation, were investigated. Our findings revealed that T3 upregulates 1,4,5-trisphosphate receptor 3 via thyroid hormone receptor α. This boosts mitochondrial Ca uptake, reduction equivalent yield, and mitochondrial ATP production, supporting the viability and proliferation of breast cancer cells without affecting non-cancerous hTERT-HME1 or PC3 prostate carcinoma cells. Understanding the interplay between T3 signaling, organellar interaction, and breast cancer metabolism could lead to targeted therapies that exploit cancer cell vulnerabilities. Our findings highlight T3 as a crucial regulator of cancer metabolism, reinforcing its potential as a therapeutic target in breast cancer.
甲状腺激素水平升高与乳腺癌风险增加和晚期阶段有关。我们之前的工作表明，生物活性三碘甲状腺原氨酸 (T3) 通过上调钙处理蛋白来促进线粒体 ATP 产生，从而提高线粒体钙摄取和克雷布斯循环活性。在这项研究中，使用不同的细胞类型来研究 T3 是否激活钙诱导的信号通路以促进癌细胞增殖。通过活细胞成像、生化测定和分子谱分析，研究了 MCF7 和 MDA-MB-468 乳腺癌细胞、非癌细胞 hTERT-HME1 和前列腺癌 PC3 细胞之间的细胞内信号差异，这些细胞先前被发现对甲状腺激素在增殖方面不敏感。我们的研究结果表明，T3 通过甲状腺激素受体 α 上调 1,4,5-三磷酸受体 3。这增加了线粒体钙摄取、还原当量产量和线粒体 ATP 产生，支持乳腺癌细胞的存活和增殖，而不影响非癌细胞 hTERT-HME1 或前列腺癌 PC3 细胞。了解 T3 信号、细胞器相互作用和乳腺癌代谢之间的相互作用可能导致利用癌细胞脆弱性的靶向治疗。我们的研究结果强调了 T3 作为癌症代谢的关键调节剂的作用，这增强了它在乳腺癌治疗中的潜在作用。
