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Folic acid depletion along with inhibition of the PERK arm of endoplasmic reticulum stress pathway promotes a less aggressive phenotype of hepatocellular carcinoma cells

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Abstract

Folate is a vital vitamin involved in one-carbon metabolism and any changes in folate status may lead to epigenetic alterations. It is already known that stages and liver cancer progression are negatively correlated with folate levels. Nevertheless, mechanisms involved in folate deficiency in HCC (Hepatocellular carcinoma) are still not completely understood. So, this study tests the hypothesis that due to the increased demand for ER (endoplasmic reticulum) proteins, folate deficiency might lead to the induction of UPR (unfolded protein response), which is further correlated with HCC outcomes. HCC cells were cultured in both folate normal (FN) and folate deficient (FD) conditions and the expression of genes of ER stress pathway was investigated. The results demonstrated activation of UPR via induction of PERK, ATF4, and LAMP3. Besides this, FD reduced the migratory capacity and the invasiveness of HCC cells along with the reduction in mesenchymal markers like vimentin but increased apoptosis. Treatment with GSK2606414 (PERK inhibitor) decreased the FD induced expression of PERK, ATF4, and LAMP3 in FD cells. Also, GSK2606414 was found to increase apoptotic cell death and to further reduce the cancer hallmarks selectively in FD cells but not in FN cells. Altogether, our data suggest that targeting the ER stress pathway along with folate deficiency may provide a more promising elimination of the metastatic potential of HCC cells contributing to more effective therapeutic agents.

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Enquiries about data availability should be directed to the authors.

Abbreviations

PERK:

Protein kinase R (PKR)-like endoplasmic reticulum kinase

ATF4:

Activating transcription factor 4

LAMP3:

Lysosome-associated membrane glycoprotein 3

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Acknowledgements

We are so grateful to Mr. Ravjit Singh (Senior Lab Technician) for his help in flow cytometry analysis.

Funding

We are thankful to DST-FIST for the sponsorship of the flow cytometry facility.

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Authors and Affiliations

  1. Department of Biochemistry, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India

    Himanshi Goyal, Renuka Sharma, Dikshit Lamba & Jyotdeep Kaur

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  1. Himanshi Goyal
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  2. Renuka Sharma
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Contributions

HG: Writing-original draft, Methodology, Data curation. RS: Supervision, Investigation, Visualization. DL: Software, Validation. JK: Conceptualization.

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Correspondence to Jyotdeep Kaur.

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Goyal, H., Sharma, R., Lamba, D. et al. Folic acid depletion along with inhibition of the PERK arm of endoplasmic reticulum stress pathway promotes a less aggressive phenotype of hepatocellular carcinoma cells. Mol Cell Biochem 478, 2057–2068 (2023). https://doi.org/10.1007/s11010-022-04651-6

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  • DOI: https://doi.org/10.1007/s11010-022-04651-6

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