Kanai Mina, Shinagawa Akiho, Ota Masako, Virgona Nantiga, Yano Tomohiro
Laboratory of Molecular Bromacology, Graduate School of Food Life Sciences, Toyo University, Gunma, Japan.
Department of Sport Medicine and Research, Japan Institute of Sports Sciences, Tokyo, Japan.
Anticancer Res. 2024 Dec;44(12):5283-5292. doi: 10.21873/anticanres.17356.
BACKGROUND/AIM: Stem-like cancer cells are believed to be the leading cause of therapy resistance in malignant melanoma (MM). All-trans retinoic acid (ATRA) differentiation therapy is considered a promising approach to eradicate stem-like cancer cells, but some melanoma cells are resistant to ATRA. This study aimed to examine whether resveratrol (RS), a natural polyphenol compound, could improve the response of MM stem-like cells to ATRA and explore the possible underlying mechanisms.
MM stem-like cells were established from a spheroid model of A375 human MM cell line. The response to RES alone and in combination with ATRA, was examined through analysis of cancer stemness, cell viability, and protein expression.
The stem-like cells showed resistance to the anticancer drug docetaxel; however, the combination of RES and ATRA augmented the effects of docetaxel. Accordingly, these combinatorial effects were associated with significant inhibition of the expression levels of stemness markers CD133, OCT4, CD271, and ABCG2. The tested combinations also led to a significant increase in melanocyte differentiation marker SOX9, while efficiently suppressing the dedifferentiation marker SOX10. Notably, RES alone effectively up-regulated retinoic acid receptor beta (RARβ) expression and down-regulated crucial mediators like DNMT1, polycomb-group proteins EZH2, and BMI-1, which mechanistically explain how RES enhanced the differentiation-inducing effects of ATRA.
The resistance of MM stem-like cells to ATRA can be attenuated by RES and combined applications of ATRA and RES provide a promising strategy for MM treatment.
背景/目的：干细胞样癌细胞被认为是恶性黑色素瘤（MM）治疗耐药的主要原因。全反式维甲酸（ATRA）分化疗法被认为是根除干细胞样癌细胞的一种有前景的方法，但一些黑色素瘤细胞对ATRA耐药。本研究旨在探讨天然多酚化合物白藜芦醇（RS）是否能改善MM干细胞样细胞对ATRA的反应，并探索可能的潜在机制。
从A375人MM细胞系的球体模型中建立MM干细胞样细胞。通过分析癌症干性、细胞活力和蛋白质表达，检测单独使用RES以及RES与ATRA联合使用时的反应。
干细胞样细胞对抗癌药物多西他赛耐药；然而，RES与ATRA联合增强了多西他赛的作用。因此，这些联合作用与干性标志物CD133、OCT4、CD271和ABCG2表达水平的显著抑制有关。所测试的联合用药还导致黑素细胞分化标志物SOX9显著增加，同时有效抑制去分化标志物SOX10。值得注意的是，单独使用RES可有效上调维甲酸受体β（RARβ）表达，并下调关键介质如DNMT1、多梳蛋白组蛋白EZH2和BMI-1，这从机制上解释了RES如何增强ATRA的诱导分化作用。
RES可减弱MM干细胞样细胞对ATRA的耐药性，ATRA与RES联合应用为MM治疗提供了一种有前景的策略。
