背景:滤泡性甲状腺癌(FTC)是分化型甲状腺癌的一种常见形式,而间变性甲状腺癌(ATC)代表一种罕见的,快速增长,未分化,和高度侵袭性的肿瘤,对根除带来重大挑战。Ferroptosis,由活性氧和随后的脂质过氧化的过度产生驱动的铁依赖性细胞死亡机制,成为一种有前途的癌症治疗策略。已经观察到许多癌细胞表现出对铁性凋亡的敏感性,而其他一些组织型似乎具有抗性,通过抵抗铁过载引起的代谢变化和氧化应激。
方法:这里我们使用人体活检和体外方法来分析铁依赖性细胞死亡的影响。我们通过MTT转换评估细胞增殖和活力,克隆检测,和细胞荧光辅助分析。脂质过氧化测定和蛋白质印迹用于分析铁凋亡调节的分子机制。两种不同的甲状腺癌细胞系,FTC-133(卵泡)和8505C(间变性),被利用。这些细胞系被暴露于铁凋亡诱导物,Erastin和RSL3,同时使用柠檬酸铁铵模拟铁过载条件。
结果:我们的证据表明FTC-133细胞系,暴露于铁过载,降低了它们的活力,并显示出增加的铁细胞凋亡。相比之下,8505C细胞系似乎能更好地耐受铁凋亡,通过调节CD71做出反应,CD71参与铁内化,似乎在抵抗铁过载并因此维持细胞活力中起作用。
结论:在我们的研究中观察到的对铁中毒的不同耐受性可能具有临床意义,特别是在解决与ATC治疗相关的未满足的治疗需求方面,与FTC相比,对铁中毒的抗性似乎更明显。
Follicular thyroid cancer (FTC) is a prevalent form of differentiated thyroid cancer, whereas anaplastic thyroid cancer (ATC) represents a rare, fast-growing, undifferentiated, and highly aggressive tumor, posing significant challenges for eradication. Ferroptosis, an iron-dependent cell death mechanism driven by the excessive production of reactive oxygen species and subsequent lipid peroxidation, emerges as a promising therapeutic strategy for cancer. It has been observed that many cancer cells exhibit sensitivity to ferroptosis, while some other histotypes appear to be resistant, by counteracting the metabolic changes and oxidative stress induced by iron overload.
Here we used human biopsies and in vitro approaches to analyse the effects of iron-dependent cell death. We assessed cell proliferation and viability through MTT turnover, clonogenic assays, and cytofluorimetric-assisted analysis. Lipid peroxidation assay and western blot were used to analyse molecular mechanisms underlying ferroptosis modulation. Two distinct thyroid cancer cell lines, FTC-133 (follicular) and 8505C (anaplastic), were utilized. These cell lines were exposed to ferroptosis inducers, Erastin and RSL3, while simulating an iron overload condition using ferric ammonium citrate.
Our evidence suggests that FTC-133 cell line, exposed to iron overload, reduced their viability and showed increased ferroptosis. In contrast, the 8505C cell line seems to better tolerate ferroptosis, responding by modulating
CD71, which is involved in iron internalization and seems to have a role in resistance to iron overload and consequently in maintaining cell viability.
The differential tolerance to ferroptosis observed in our study may hold clinical implications, particularly in addressing the unmet therapeutic needs associated with ATC treatment, where resistance to ferroptosis appears more pronounced compared to FTC.