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SRGAP2 controls colorectal cancer chemosensitivity via regulation of mitochondrial complex I activity

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Abstract

Mitochondrial respiration and metabolism play an important role in the occurrence and development of colorectal cancer (CRC). In this study, we identified a functional pool of SLIT–ROBO Rho GTPase-activating protein 2 (SRGAP2) in the mitochondria of CRC cells as an important regulator of CRC chemosensitivity. We found that SRGAP2 levels were increased in CRC cells in comparison to normal colorectal cells. Loss of mitochondrial SRGAP2 led to significant decrease in mitochondrial respiration and strongly sensitized the CRC cells to chemotherapy drugs. Mechanistically, SRGAP2 physically interacts with mitochondrial complex I and positively modulates its activity. In particular, chemosensitization upon SRGAP2 loss was phenocopied by the treatment of complex I inhibitor. Thus, our results demonstrate that SRGAP2 functions as a key regulator of CRC chemosensitivity, identifying SRGAP2 as a promising therapeutic target to enhance the efficacy of chemotherapy in CRC.

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Data Availability Statement

CRC transcriptome sequencing data and corresponding clinical data set were downloaded from TCGA (https://cancergenome.nih.gov, TCGA–COAD and TCGA–READ).

Abbreviations

CRC:

Colorectal cancer

TCGA:

The Cancer Genome Atlas

OCR:

Oxygen consumption rate

MTS:

Mitochondrial targeting signal

NLS:

Nuclear localization sequence

SRB:

Sulforhodamine B

5-FU:

5-Flourouracil

3’ UTR:

3′ Untranslated region

EV:

Empty vector

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Acknowledgements

We thank the TCGA Research Network for providing its platforms and valuable data sets.

Funding

This present study was funded by Key Research and Development Project of Chuzhou (Grant no. 2020ZN007).

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Author notes

  1. Yongqin Tang and Guijun Liu have contributed equally to this work and share first authorship.

Authors and Affiliations

  1. Department of Gastrointestinal Surgery, The Affiliated Chuzhou Hospital of Anhui Medical University, The First People’s Hospital of Chuzhou, Chuzhou, China

    Yongqin Tang & Tao Sun

  2. Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China

    Guijun Liu & Yanhan Jia

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  1. Yongqin Tang
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Contributions

TY, LG, JY, and ST were responsible for the concept and design of the original study. TY and LG performed the experiments and analysed data. JY and ST wrote the paper with input from all authors. All authors contributed to the article and approved the submitted version.

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Correspondence to Yanhan Jia or Tao Sun.

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Tang, Y., Liu, G., Jia, Y. et al. SRGAP2 controls colorectal cancer chemosensitivity via regulation of mitochondrial complex I activity. Human Cell 35, 1928–1938 (2022). https://doi.org/10.1007/s13577-022-00781-7

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