CD147 confers temozolomide resistance of glioma cells via the regulation of β-TrCP/Nrf2 pathway

被引：23

作者：

Bu, Xin ^{[1
]}

Qu, Xuan ^{[2
]}

Guo, Kai ^{[3
]}

Meng, Xiangliang ^{[1
]}

Yang, Xing ^{[4
,11
]}

Huang, Qike ^{[5
]}

Dou, Wenjie ^{[6
]}

Feng, Lin ^{[7
]}

Wei, Xinxin ^{[8
]}

Gao, Jiwei ^{[9
]}

Sun, Wei ^{[10
]}

Chao, Min ^{[11
]}

Han, Liying ^{[11
]}

Hu, Yaqin ^{[11
]}

Shen, Liangliang ^{[1
]}

Zhang, Jian ^{[1
]}

Wang, Liang ^{[11
]}

机构：

[1] Fourth Mil Med Univ, Dept Biochem & Mol Biol, State Key Lab Canc Biol, Xian 710032, Shaanxi, Peoples R China

[2] Shaanxi Univ Chinese Med, Xianyang 712046, Peoples R China

[3] Fourth Mil Med Univ, Xijing Hosp, Dept Burns & Cutaneous Surg, Xian 710032, Peoples R China

[4] JingKai 3 Middle Sch, Xian 710200, Peoples R China

[5] Naval Med Univ, Eastern Hepatobiliary Hosp, Dept Hepat Surg 3, Shanghai 200438, Peoples R China

[6] Fourth Mil Med Univ, Xijing Hosp, Dept Plast & Reconstruct Surg, Xian 710032, Peoples R China

[7] Jiamusi Univ, Basic Med Coll, Jiamusi 154002, Peoples R China

[8] Jiamusi Univ, Hosp Stomatol, Dept Oral & Maxillofacial Surg, Jiamusi 154002, Peoples R China

[9] Fourth Mil Med Univ, Tangdu Hosp, Dept Gen Surg, Xian 710038, Peoples R China

[10] PLA Tibet Mil Area Command, Gen Hosp, Dept Anorectal, Lhasa 850007, Peoples R China

[11] Fourth Mil Med Univ, Tangdu Hosp, Dept Neurosurg, Xian 710038, Shaanxi, Peoples R China

来源：

INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES | 2021年 / 17卷 / 12期

基金：

中国国家自然科学基金;

关键词：

CD147; Temozolomide; Glioma; beta-TrCP; Nrf2; NF-KAPPA-B; MELANOMA-CELLS; NRF2; APOPTOSIS;

D O I：

10.7150/ijbs.60894

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Background: Drug resistance is one of the biggest challenges in cancer therapy. temozolomide (TMZ) represents the most important chemotherapeutic option for glioma treatment. However, the therapeutic efficacy of TMZ remains very limited due to its frequent resistance in glioma, and the underlying mechanisms were not fully addressed. Herein, we demonstrate that the elevated expression of CD147 contributes to TMZ resistance in glioma cells, potentially through the post-translational regulation of Nrf2 expression. Methods: Cell-based assays of CD147 triggered drug resistance were performed through Edu-incorporation assay, CCK8 assay, TUNEL staining assay and flow cytometric assay. Luciferase reporter assay, protein stability related assays, co-immunoprecipitation assay were used to determine CD147 induction of Nrf2 expression through beta-TrCP dependent ubiquitin system. Finally, the effect of the CD147/Nrf2 signaling on glioma progression and TMZ resistance were evaluated by functional experiments and clinical samples. Results: Based on the analysis of clinical glioma tissues, CD147 is highly expressed in glioma tissues and positively associated with tumor malignancy. Suppression of CD147 expression increased the inhibitory effect of TMZ on cell survival in both U251 and T98G cells, whereas the gain of CD147 function blocked TMZ-induced ROS production and cell death. Mechanistic study indicates that CD147 inhibited GSK3 beta/beta-TrCP-dependent Nrf2 degradation by promoting Akt activation, and subsequently increased Nrf2-mediated anti-oxidant gene expressions. Supporting the biological significance, the reciprocal relationship between CD147 and Nrf2 was observed in glioma tissues, and associated with patient outcome. Conclusions: Our data provide the first evidence that glioma resistance to TMZ is potentially due to the activation of CD147/Nrf2 axis. CD147 promotes Nrf2 stability through the suppression of GSK3 beta/beta-TrCP dependent Nrf2 protein degradation, which results in the ablation of TMZ induced ROS production. As such, we point out that targeting CD147/Nrf2 axis may provide a new strategy for the treatment of TMZ resistant gliomas.

引用

页码：3013 / 3023

页数：11

共 33 条

[31] Inhibition of NF-κB results in anti-glioma activity and reduces temozolomide-induced chemoresistance by down-regulating MGMT gene expression [J].

Yu, Zhiyun ;

Chen, Yong ;

Wang, Shiqiang ;

Li, Pengliang ;

Zhou, Guangtong ;

Yuan, Yongjie .

CANCER LETTERS, 2018, 428 :77-89

[32] The Dark Side of Nrf2 in the Heart [J].

Zang, Huimei ;

Mathew, Roy Oomen ;

Cui, Taixing .

FRONTIERS IN PHYSIOLOGY, 2020, 11

[33] CD147 promotes DNA damage response and gemcitabine resistance via targeting ATM/ATR/p53 and affects prognosis in pancreatic cancer [J].

Zhou, Yinghui ;

Zheng, Ming ;

Liu, Zhenyu ;

Yang, Haijiao ;

Zhu, Ping ;

Jiang, Jian-Li ;

Tang, Juan ;

Chen, Zhi-Nan .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2020, 528 (01) :62-70

← 1 2 3 4 →