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Recycling of SLC38A1 to the plasma membrane by DSCR3 promotes acquired temozolomide resistance in glioblastoma

  • Laboratory Investigation
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Purpose

Glioblastoma multiforme (GBM) is a primary brain tumor with devastating prognosis. Although the O6-methylguanine-DNA methyltransferase (MGMT) leads to inherent temozolomide (TMZ) resistance, approximately half of GBMs were sufficient to confer acquired TMZ resistance, which express low levels of MGMT. The purpose of this study was to investigate the underlying mechanisms of the acquired TMZ resistance in MGMT-deficient GBM.

Methods

The function of Down syndrome critical region protein 3 (DSCR3) on MGMT-deficient GBM was investigated in vitro and in an orthotopic brain tumor model in mice. Purification of plasma membrane proteins by membrane-cytoplasmic separation and subsequent label free-based quantitative proteomics were used to identified potential protein partners for DSCR3. Immunofluorescence was performed to show the reverse transport of solute carrier family 38 member 1 (SLC38A1) mediated by DSCR3.

Results

DSCR3 is upregulated in MGMT-deficient GBM cells during TMZ treatment. Both DSCR3 and SLC38A1 were highly expressed in recurrent GBM patients. Silencing DSCR3 or SLC38A1 expression can increase TMZ sensitivity in MGMT-deficient GBM cells. Combination of proteomics and in vitro experiments show that DSCR3 directly binds internalized SLC38A1 to mediate its sorting into recycling pathway, which maintains the abundance on plasma membrane and enhances uptake of glutamine in MGMT-deficient GBM cells.

Conclusions

DSCR3 is a crucial regulator of acquired TMZ resistance in MGMT-deficient GBM. The DSCR3-dependent recycling of SLC38A1 maintains its abundance on plasma membrane, leading to tumor progression and acquired TMZ resistance in MGMT-deficient GBM.

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Data availability

The datasets generated and analysed during the current study are available from the corresponding author on reasonable request.

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Funding

This study was supported by the Natural Science Foundation of Guangdong Province, the National Natural Science Foundation of China (Grant Nos. 81803100), Key R&D Program of Guangdong Province (2018B090906001), Outstanding Youth Development Scheme of Nanfang Hospital, Southern Medical University (2019J002) and Young innovative talents in Colleges and Universities in Guangdong Province (2021KQNCX022).

Author information

Author notes

  1. Rui Lin and Yimin Xu have contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou Dadao Bei Street, Guangzhou, 510515, Guangdong, People’s Republic of China

    Rui Lin, Sidi Xie, Hai Wang, Guo-Zhong Yi, Guanglong Huang, Song-Tao Qi & Yawei Liu

  2. The Laboratory for Precision Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, People’s Republic of China

    Rui Lin, Sidi Xie, Yunxiao Zhang, Bowen Ni, Haimin Song, Ziyu Wang, Song-Tao Qi & Yawei Liu

  3. Department of Neurosurgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, Guangdong, People’s Republic of China

    Rui Lin & Yimin Xu

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  1. Rui Lin
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Contributions

RL was the major contributor in experiments performing and manuscript writing. YX was the major contributor in experiments performing. YL and S-TQ were the contributors of the design of the study. SX, YZ, BN, G-ZY and GH were the major contributors in data acquisition and specimen collection. SX, YZ, HW, BN, HS, ZW were contributors in experiments performing and analysis presentation. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Song-Tao Qi or Yawei Liu.

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Conflict of interest

The authors report no competing interests.

Ethical approval

Ethics of animal and human research subjects has been reviewed by the Ethics Committee of Southern Medical University. Animal care complied with the Guide for the Care and Use of Laboratory Animals. For patient material, written consent will be sought from all participants prior to their inclusion in the study.

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Informed consent was obtained from all individual participants included in the study.

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Patients signed informed consent regarding publishing their anonymized data and photographs.

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Lin, R., Xu, Y., Xie, S. et al. Recycling of SLC38A1 to the plasma membrane by DSCR3 promotes acquired temozolomide resistance in glioblastoma. J Neurooncol 157, 15–26 (2022). https://doi.org/10.1007/s11060-022-03964-2

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  • DOI: https://doi.org/10.1007/s11060-022-03964-2

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