鑭及鈰抑制乳癌細胞生長之機制探討

Abstract

稀土元素鑭(Lanthanum)和鈰(Cerium)，其物理特性皆與鈣(Calcium)相似，若使用恰當，普遍被認為無毒性。而我們於前人的研究中發現鑭離子具有抗腫瘤調節的能力，因癌細胞內的酸性環境可助於的鑭及鈰解離，並以模擬鈣的形式干擾細胞生長。而本研究選用三陰性的乳腺癌細胞系MDA-MB-231，此種乳腺癌容易早期轉移，只能透過化療治癒。因此，我們透過檢測與核醣體生合成相關之因素及氧化壓力所造成的細胞損害以探討鑭及鈰是否會影響MDA-MB-231生長及其他造成毒性的機制。實驗結果顯示鑭及鈰會干擾rRNA的加工和核醣體生合成，其中也發現鑭及鈰對核醣體大次單元的影響更大，並且造成p53依賴性及非依賴性的核仁壓力。鑭及鈰的處理下也會誘導氧化壓力造成粒線體功能障礙及導致蛋白質氧化，而這些氧化的蛋白質可能因蛋白酶體無法發揮功能而在細胞中累積並誘導自噬作用。而由次世代定序的結果也發現細胞骨架相關基因受到影響，透過免疫螢光實驗可見到細胞經處理後導致F-actin聚集，表示細胞貼附可能受到影響。另外，我們也發現順鉑和鑭或鈰的處理下能產生加成性，抑制MDA-MB-231的生長及抗藥性相關的基因。本研究探討類鈣元素鑭及鈰抑制乳腺癌細胞生長之機制，其中核仁壓力及氧化壓力為造成細胞生長抑制之主因。

The rare earth elements lanthanum (La) and cerium (Ce) have similar physical properties to calcium (Ca) and are generally considered non-toxic if appropriately used. But La and Ce ions have the anti-tumor ability because the acidic environment in cancer cells can help the dissociation of La and Ce and interfere with cell growth in competition with Ca. In this study, the triple-negative breast cancer cell line MDA-MB-231 was selected, which is prone to early metastasis and can only be cured by chemotherapy. Therefore, we investigated a mechanism study about how La and Ce affect MDA-MB-231. The results show that La and Ce interfere with rRNA processing and ribosome biosynthesis and cause p53-dependent and independent nucleolar stress. La and Ce also induce oxidative stress through mitochondrial dysfunction, leading to protein oxidation. Autophagy is induced while the proteasome function is also impaired. The results of Next-Generation Sequencing (NGS) also found that cytoskeleton-related genes were affected. Immunofluorescence experiments showed that F-actin aggregated after cells were treated, indicating that cell adhesion may be affected. In addition, the co-treatment of cisplatin with La or Ce showed synergistic inhibition of growth and drug resistance-related genes in MDA-MB-231 cells. This study investigated the mechanism of the calcium-like elements La and Ce in inhibiting the growth of breast cancer cells. We found that nucleolar stress and oxidative stress were the main reasons for cell growth inhibition.