Arginine regulates HSPA5/BiP translation through ribosome pausing in triple-negative breast cancer cells

Background Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a high mortality rate due to a lack of therapeutic targets. Many TNBC cells are reliant on extracellular arginine for survival and express high levels of binding immunoglobin protein (BiP), a marker of met...

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Bibliographic Details
Published in:British journal of cancer 2023-08, Vol.129 (3), p.444-454
Main Authors: Vidal, Christina M., Ouyang, Ching, Qi, Yue, Mendez-Dorantes, Carlos, Coblentz, Alaysia, Alva-Ornelas, Jackelyn A., Stark, Jeremy M., Seewaldt, Victoria L., Ann, David K.
Format: Article
Language:English
Subjects:
631/337/574
631/67/2327
Arginine
Biomedical and Life Sciences
Biomedicine
Breast cancer
Cancer Research
Codons
Drug Resistance
Endoplasmic reticulum
Epidemiology
GRP78 protein
Metastases
Molecular Medicine
Oncology
Therapeutic targets
Translation
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Summary:Background Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a high mortality rate due to a lack of therapeutic targets. Many TNBC cells are reliant on extracellular arginine for survival and express high levels of binding immunoglobin protein (BiP), a marker of metastasis and endoplasmic reticulum (ER) stress response. Methods In this study, the effect of arginine shortage on BiP expression in the TNBC cell line MDA-MB-231 was evaluated. Two stable cell lines were generated in MDA-MB-231 cells: the first expressed wild-type BiP, and the second expressed a mutated BiP free of the two arginine pause-site codons, CCU and CGU, termed G-BiP. Results The results showed that arginine shortage induced a non-canonical ER stress response by inhibiting BiP translation via ribosome pausing. Overexpression of G-BiP in MDA-MB-231 cells promoted cell resistance to arginine shortage compared to cells overexpressing wild-type BiP. Additionally, limiting arginine led to decreased levels of the spliced XBP1 in the G-BiP overexpressing cells, potentially contributing to their improved survival compared to the parental WT BiP overexpressing cells. Conclusion In conclusion, these findings suggest that the downregulation of BiP disrupts proteostasis during arginine shortage-induced non-canonical ER stress and plays a key role in cell growth inhibition, indicating BiP as a target of codon-specific ribosome pausing upon arginine shortage.
ISSN:0007-0920
1532-1827
DOI:10.1038/s41416-023-02322-x