Department of Molecular and Medical Pharmacology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Department of Thoracic and Breast Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Cancer Sci. 2023 Nov;114(11):4355-4364. doi: 10.1111/cas.15949. Epub 2023 Sep 8.
Accumulating evidence suggests an association between iron metabolism and lung cancer progression. In biological systems, iron is present in either reduced (Fe ; ferrous) or oxidized (Fe ; ferric) states. However, ferrous and ferric iron exhibit distinct chemical and biological properties, the role of ferrous and ferric iron in lung cancer cell growth has not been clearly distinguished. In this study, we manipulated the balance between cellular ferrous and ferric iron status by inducing gene mutations involving the FBXL5-IRP2 axis, a ubiquitin-dependent regulatory system for cellular iron homeostasis, and determined its effects on lung cancer cell growth. FBXL5 depletion (ferrous iron accumulation) was found to suppress lung cancer cell growth, whereas IRP2 depletion (ferric iron accumulation) did not suppress such growth, suggesting that ferrous iron but not ferric iron plays a suppressive role in cell growth. Mechanistically, the depletion of FBXL5 impaired the degradation of the cyclin-dependent kinase inhibitor, p27, resulting in a delay in the cell cycle at the G1/S phase. FBXL5 depletion in lung cancer cells also improved the survival of tumor-bearing mice. Overall, this study highlights the important function of ferrous iron in cell cycle progression and lung cancer cell growth.
越来越多的证据表明，铁代谢与肺癌的进展有关。在生物系统中，铁以还原态（Fe ；二价铁）或氧化态（Fe ；三价铁）存在。然而，二价铁和三价铁具有明显不同的化学和生物学特性，二价铁和三价铁在肺癌细胞生长中的作用尚未明确区分。在这项研究中，我们通过诱导涉及 FBXL5-IRP2 轴的基因突变来操纵细胞内二价铁和三价铁状态的平衡，FBXL5-IRP2 轴是细胞铁稳态的一个依赖泛素的调节系统，并确定其对肺癌细胞生长的影响。FBXL5 的耗竭（二价铁积累）被发现抑制肺癌细胞的生长，而 IRP2 的耗竭（三价铁积累）并没有抑制这种生长，这表明二价铁而不是三价铁在细胞生长中起抑制作用。从机制上讲，FBXL5 的耗竭会损害细胞周期蛋白依赖性激酶抑制剂 p27 的降解，导致细胞周期在 G1/S 期停滞。肺癌细胞中 FBXL5 的耗竭也改善了荷瘤小鼠的存活。总的来说，这项研究强调了二价铁在细胞周期进程和肺癌细胞生长中的重要功能。
