TRAF inhibition drives cancer cell apoptosis and improves retinoic acid sensitivity in multiple cancers models.
TRAF inhibition drives cancer cell apoptosis and improves retinoic acid sensitivity in multiple cancers models.
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DOI：
10.1007/s12672-023-00703-5
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发表时间：
2023-06-30
影响因子：
2.2
通讯作者：
Gu, Yayun
中科院分区：
文献类型：
--
作者：
Zhong, Kun;Liu, Xiaojun;Ding, Weihua;Peng, Lizhong;Zeng, Xuhui;Gu, Yayun
肿瘤坏死因子受体相关因子（TNF receptor-associated factors，TRAFs）是一种信号调节蛋白，在调节细胞受体信号传导至下游通路中起着重要作用，在调节信号通路、细胞存活和肿瘤发生中发挥着多方面的作用。13-顺式维甲酸（RA）是维生素A的活性代谢产物，具有抗癌活性，但维甲酸耐药性的产生给临床应用带来了挑战。本研究旨在探讨TRAFs和维甲酸敏感性之间的关系，在各种癌症。在这里，我们揭示了TRAFs的表达在癌症基因组图谱（TCGA）癌症队列和人类癌细胞系中存在显著差异。此外，抑制TRAF 4、TRAF 5或TRAF 6可改善卵巢癌和黑素瘤细胞对视黄酸的敏感性并减少集落形成。机械地，在视黄酸处理的癌细胞系中敲低TRAF 4、TRAF 5或TRAF 6增加了半胱氨酸天冬氨酸蛋白酶原9的水平并诱导细胞凋亡。使用SK-0 V-3和MeWo异种移植物模型的进一步体内研究证实了TRAF敲低与视黄酸处理组合的抗肿瘤作用。这些发现支持了维甲酸和TRAF沉默的联合疗法可以在治疗黑色素瘤和卵巢癌中提供显著的治疗优势。在线版本包含补充材料，可通过10.1007/s12672-023-00703-5获得。
TNF receptor-associated factors (TRAFs) are signaling adaptor proteins that play a crucial role in regulating cellular receptors’ signaling transduction to downstream pathways and exert multifaceted roles in regulating signaling pathways, cell survival, and carcinogenesis. The 13-cis-retinoic acid (RA), an active metabolite of vitamin A, exhibits anti-cancer properties, but the development of retinoic acid resistance poses a challenge in clinical application. This study aimed to investigate the relationship between TRAFs and retinoic acid sensitivity in various cancers. Here, we revealed that TRAFs’ expression varied significantly across The Cancer Genome Atlas (TCGA) cancer cohorts and human cancer cell lines. Additionally, inhibiting TRAF4, TRAF5, or TRAF6 improved retinoic acid sensitivity and reduced colony formation in ovarian cancer and melanoma cells. Mechanistically, knocking down TRAF4, TRAF5, or TRAF6 in retinoic acid-treated cancer cell lines increased the levels of procaspase 9 and induced cell apoptosis. Further in vivo studies using the SK-OV-3 and MeWo xenograft models confirmed the anti-tumor effects of TRAF knockdown combined with retinoic acid treatment. These findings support that combination therapy with retinoic acid and TRAF silencing may offer significant therapeutic advantages in treating melanoma and ovarian cancers. The online version contains supplementary material available at 10.1007/s12672-023-00703-5.
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