Oleanolic acid inhibits aldo-keto reductase family 1 member B10-induced cancer stemness and avoids cisplatin-based chemotherapy resistance via the Snail signaling pathway in oral squamous cell carcinoma cell lines

IF 3.4 3区医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE

Journal of Dental Sciences Pub Date : 2025-01-01 DOI:10.1016/j.jds.2024.09.018

Hui-Hsin Ko , Han-Yi E. Chou , Hsin-Han Hou , Wei-Ting Kuo , Wei-Wen Liu , Mark Yen-Ping Kuo , Shih-Jung Cheng

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引用次数: 0

Abstract

Background/purpose

Oral squamous cell carcinoma (OSCC) is a common malignancy often associated with poor prognosis due to chemoresistance. In this study, we investigated whether arecoline, a major alkaloid in betel nuts, can stimulate aldo-keto reductase family 1 member B10 (AKR1B10) levels in OSCC, promoting cancer stemness and leading to resistance to cisplatin (CDDP)-based chemotherapy.

Materials and methods

Gain- and Loss- of AKR1B10 functions were analyzed using WB and q-PCR of OSCC cells. Stemness, epithelial mesenchymal transition (EMT) markers, and CDDP drug resistance in overexpressed AKR1B10 were also identified.

Results

Upregulated AKR1B10 in OSCC significantly increased cell motility and aggregation. The results also showed that the canonical TGF-β1-Smad3 pathway was involved in arecoline-induced AKR1B10 expression, further increasing cancer stemness with CDDP resistance via the Snail-dependent EMT pathway. Moreover, oleanolic acid (OA) and ROS/RNS (reactive oxygen/nitrogen species) inhibitors effectively reversed AKR1B10-induced CDDP-resistance.

Conclusion

Arecoline-induced ROS/RNS to hyper-activate AKR1B10 in tumor sphere cells via the TGF-β1-Smad3 pathway. Furthermore, AKR1B10 enhanced CDDP resistance in OSCC cells via EMT-inducing markers. Finally, Finally, OA may efficiently target CDDP resistance, reverse stemness in OSCC cells, and have the potential as a novel anticancer drug.

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齐墩果酸能抑制醛酮还原酶家族1成员B10诱导的癌症干性，并通过蜗牛信号通路避免口腔鳞状细胞癌细胞株对顺铂化疗产生耐药性。

背景/目的：口腔鳞状细胞癌（OSCC）是一种常见的恶性肿瘤，常因化疗耐药而导致预后不良。在这项研究中，我们探讨了槟榔中的一种主要生物碱--山豆根碱（arecoline）能否刺激 OSCC 中醛酮还原酶家族 1 成员 B10（AKR1B10）的水平，从而促进癌症干性并导致对以顺铂（CDDP）为基础的化疗产生耐药性：采用WB和q-PCR对OSCC细胞进行AKR1B10功能的增益和缺失分析。此外，还鉴定了过表达 AKR1B10 细胞的干性、上皮间质转化（EMT）标记和 CDDP 耐药性：结果：OSCC中AKR1B10的上调明显增加了细胞的运动性和聚集性。结果表明：AKR1B10在OSCC中的上调可明显增加细胞的运动性和聚集性，还表明TGF-β1-Smad3典型通路参与了arecoline诱导的AKR1B10表达，并通过蜗牛依赖的EMT通路进一步增加癌症干性和CDDP耐药性。此外，齐墩果酸（OA）和ROS/RNS（活性氧/氮物种）抑制剂能有效逆转AKR1B10诱导的CDDP抗性：结论：Arecoline通过TGF-β1-Smad3通路诱导ROS/RNS过度激活肿瘤球细胞中的AKR1B10。此外，AKR1B10 还能通过 EMT 诱导标记增强 OSCC 细胞对 CDDP 的耐药性。最后，OA可有效靶向CDDP耐药性，逆转OSCC细胞的干性，有望成为一种新型抗癌药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Dental Sciences 医学-牙科与口腔外科

CiteScore

5.10

自引率

14.30%

发文量

348

审稿时长

6 days

期刊介绍： he Journal of Dental Sciences (JDS), published quarterly, is the official and open access publication of the Association for Dental Sciences of the Republic of China (ADS-ROC). The precedent journal of the JDS is the Chinese Dental Journal (CDJ) which had already been covered by MEDLINE in 1988. As the CDJ continued to prove its importance in the region, the ADS-ROC decided to move to the international community by publishing an English journal. Hence, the birth of the JDS in 2006. The JDS is indexed in the SCI Expanded since 2008. It is also indexed in Scopus, and EMCare, ScienceDirect, SIIC Data Bases. The topics covered by the JDS include all fields of basic and clinical dentistry. Some manuscripts focusing on the study of certain endemic diseases such as dental caries and periodontal diseases in particular regions of any country as well as oral pre-cancers, oral cancers, and oral submucous fibrosis related to betel nut chewing habit are also considered for publication. Besides, the JDS also publishes articles about the efficacy of a new treatment modality on oral verrucous hyperplasia or early oral squamous cell carcinoma.