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Theranostics 2022; 12(9):4330-4347. doi:10.7150/thno.71763 This issue Cite

Research Paper

PTRF/Cavin-1 enhances chemo-resistance and promotes temozolomide efflux through extracellular vesicles in glioblastoma

Eryan Yang^1,2, Lin Wang^1,2, Weili Jin^1,2, Xing Liu³, Qixue Wang^1,2, Ye Wu^1,2, Yanli Tan^4,5,7, Yunfei Wang^1,2, Xiaoteng Cui^1,2, Jixing Zhao^1,2, Fei Tong^1,2, Biao Hong^1,2, Menglin Xiao^6,7, Xiaomin Liu^8✉, Chuan Fang^6,7✉, Chunsheng Kang^1,2✉

1. Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China
2. Tianjin Neurological Institute, Key Laboratory of Post-neurotrauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin 300052, China
3. Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China
4. Department of Pathology, Hebei University School of Basic Medical Sciences, Baoding 071000, China
5. Department of Pathology, Affiliated Hospital of Hebei University, Baoding 071000, China
6. Department of Neurosurgery, Affiliated Hospital of Hebei University, Baoding 071000, China
7. Key Laboratory of Precise Diagnosis and Treatment of Glioma in Hebei Province, Baoding 071000, China
8. Department of Oncology, Gamma Knife Center, Department of Neurological Surgery, Tianjin Huanhu Hospital, Nankai University, Tianjin 300350, China
These authors contributed equally to this work: Eryan Yang, Lin Wang and Weili Jin

✉ Corresponding authors: Chunsheng Kang (kang97061edu.cn); Chuan Fang (chuanfangedu.cn); Xiaomin Liu (liuxmedu.cn)

Abstract

Background: The concentration and duration of intracellular drugs have always been the key factors for determining the efficacy of the treatment. Efflux of chemotherapeutic drugs or anticancer agents is a major reason for multidrug resistance generation in cancer cells. The high expression of polymerase I and transcript release factor (PTRF) is correlated with a worse prognosis in glioma patients. However, the importance of PTRF on temozolomide (TMZ) resistance in glioblastoma (GBM) is poorly understood.

Methods: TCGA data analysis, CGGA data analysis, transmission electron microscopy (TEM), scanning electron microscopy (SEM), clone formation, cell counting kit-8 (cck-8), western blot (WB), immunofluorescence (IF), immunohistochemistry (IHC) and flow cytometry assays were performed to investigate the underlying mechanism and effect of PTRF on TMZ-resistance in a variety of GBM cell lines and GBM patient-derived xenograft (PDX) models. Clone formation, WB, IF, IHC and flow cytometry assays were performed to examine the efficacy of sequential therapy of TMZ followed by CQ in GBM cells and PDX models.

Results: The prognosis of GBM patients treated with TMZ was negatively correlated with PTRF expression. Our results reveal that PTRF knockdown significantly decrease proliferation and increase apoptosis in GBM after TMZ treatment. Moreover, PTRF contribute to TMZ-resistance by increasing TMZ efflux through extracellular vesicles (EVs). Furthermore, our results demonstrate that sequential therapy of TMZ followed by CQ significantly promotes the TMZ efficacy against GBM by increasing intracellular TMZ concentration ([TMZ]i).

Conclusion: This study highlights that PTRF can act as an independent biomarker to predict the prognosis of GBM patients after TMZ treatment and describes a new mechanism contributing to TMZ-resistance. In addition, this study may provide a novel idea for GBM therapy.

Keywords: Glioblastoma, temozolomide, PTRF, extracellular vesicles, chloroquine

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