Int J Biol Sci 2021; 17(12):3013-3023. doi:10.7150/ijbs.60894 This issue
1. The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, 710032, China.
2. Shaanxi University of Chinese Medicine, Xianyang, 712046, China.
3. Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, China.
4. JingKai NO. 3 Middle School, Xi'an, 710200, China.
5. The 3rd Department of Hepatic Surgery, Eastern Hepatobiliary Hospital, Naval Medical University, Shanghai, 200438, China.
6. Department of Plastic and Reconstructive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
7. Basic Medical College, Jiamusi University, Jiamusi, 154002, China.
8. Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jiamusi University, Jiamusi, 154002, China.
9. Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, China.
10. Department of Anorectal, the General Hospital of PLA Tibet Military Area Command, Lhasa, 850007, China.
11. Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, China.
#These authors contributed equally to this work.
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 β-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 GSK3β/β-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 GSK3β/β-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.
Keywords: CD147, Temozolomide, Glioma, β-TrCP, Nrf2