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SMAGP regulates doxorubicin sensitivity in triple-negative breast cancer cells via modulating mitochondrial respiration

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Abstract

Doxorubicin-based chemotherapy remains as a major therapeutic approach for patients with triple-negative breast cancer (TNBC). However, insensitivity or resistance to doxorubicin treatment limits the therapeutic efficacy. Mitochondrial respiration plays a critical role in regulating the sensitivity of cancer cells to chemotherapy drugs. Here, we found that small trans-membrane and glycosylated protein (SMAGP) is upregulated in TNBC cells in comparison to normal breast and other subtypes of breast cancer cells. High SMAGP expression is associated with poorer overall survival of TNBC patients. Importantly, loss of SMAGP enhanced the sensitivity of TNBC cells to doxorubicin treatment. Mechanistically, we detected a functional pool of SMAGP in the mitochondria of TNBC cells controlling doxorubicin sensitivity via regulating mitochondrial respiration. Thus, our data suggest that SMAGP acts as a novel regulator of doxorubicin sensitivity in TNBC, identifying SMAGP as a promising therapeutic target for improving the efficacy of doxorubicin-based chemotherapy in TNBC patients.

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Data availability

Publicly available dataset analyzed in this study can be found here: TCGA (https://portal.gdc.cancer.gov/).

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Acknowledgements

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

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Authors and Affiliations

  1. Department of Medical Oncology, Yantaishan Hospital, Yantai, Shandong Province, China

    Huawei Xiao, Xifeng Yang & Shaoyan Huang

Authors
  1. Huawei Xiao
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  2. Xifeng Yang
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  3. Shaoyan Huang
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Contributions

Conceptualization: HX and SH; resources: HX and SH; data curation: SH; formal analysis: HX, XY, and SH; supervision: SH; validation: HX, XY, and SH; investigation: HX and XY; visualization: HX and XY; methodology: HX and XY; project administration: SH; writing—original draft: HX; writing—review and editing: HX, XY, and SH.

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Correspondence to Shaoyan Huang.

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280_2022_4496_MOESM1_ESM.tif

Figure S1. Knockdown efficiencies of SMAGP-targeting shRNAs were determined in TNBC cells.Western blot analysis of SMAGP protein level in the indicated breast cancer cells transduced with shCtrl or two different shRNAs targeting SMAGP. (TIF 2129 kb)

280_2022_4496_MOESM2_ESM.tif

Figure S2. SMAGP depletion does not influence the cell viability, migration, or invasion of breast cancer cells. (A) Cell viabilities of various breast cancer cells transduced with shCtrl or two different SMAGP-targeting shRNAs were determined using SRB assay. (B and C) Boyden chamber-based migration (B) and invasion (C) assay were performed to determine the migratory and invasive capacities of various breast cancer cells upon transduction with shCtrl or two different shRNAs targeting SMAGP. (A-C) Data are presented as mean + SD. n = 3. Results are representative of a minimum of three independent experiments. (TIF 2327 kb)

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Xiao, H., Yang, X. & Huang, S. SMAGP regulates doxorubicin sensitivity in triple-negative breast cancer cells via modulating mitochondrial respiration. Cancer Chemother Pharmacol 91, 43–52 (2023). https://doi.org/10.1007/s00280-022-04496-2

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